JP2008519057A - Formulation of [1,4] diazepino [6,7,1-ij] quinoline derivatives - Google Patents

Abstract

  The present invention provides solid dosage formulations of [1,4] diazepino [6,7,1-ij] quinoline derivatives and methods for their preparation. In some specific embodiments, the present invention relates to antipsychotics and anti-obesity drugs (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a decahydrocyclopenta [ c] A novel formulation of [1,4] diazepino [6,7,1-ij] quinoline hydrochloride (Compound A · HCl) is provided.

Description

  The present invention relates to solid dosage formulations of [1,4] diazepino [6,7,1-ij] quinoline derivatives and methods for their production. In some specific embodiments, the present invention provides antipsychotics and anti-obesity agents (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [C] A novel formulation of [1,4] diazepino [6,7,1-ij] quinoline hydrochloride (Compound A · HCl) is provided.

Schizophrenia affects about 5 million people. At present, the most widespread treatment for schizophrenia is the “atypical” antipsychotic, which is dopamine (D2) receptor antagonism and serotonin (5-HT _2A ) receptor antagogue. Combining with nism. Despite reported improvements in the efficacy and side effect propensity of atypical antipsychotics over typical antipsychotics, these compounds adequately treat all of the symptoms of schizophrenia But with troublesome side effects including weight gain (Allison, DB, et. Al., Am. J. Psychiatry, 156: 1686-1696, 1999; Masand, PS, Exp. Opin. Pharmacother. 1: 377 -389, 2000; Whitaker, R., Spectrum Life Sciences. Decision Resources, 2: 1-9, 2000). New antipsychotics that are effective in treating mood disorders or cognitive disorders in schizophrenia without causing weight gain represent a significant advance in the treatment of schizophrenia.

5-HT _2C agonists and partial agonists are novel therapeutic approaches to the treatment of schizophrenia. Several lines of evidence support the role of 5-HT _2C receptor agonism as a treatment for schizophrenia. Studies with 5-HT _2C antagonists suggest that these compounds increase dopamine synaptic levels and may be effective in animal models of Parkinson's disease (Di Matteo, V., et al Neuropharmacology, 37: 265-272, 1998; Fox, SH, et al., Experimental Neurology, 151: 35-49, 1998). Since the positive symptoms of schizophrenia are associated with increased levels of dopamine, compounds having an effect opposite to that of 5-HT _2C antagonists, such as 5-HT _2C agonists and partial agonists, are associated with levels of synaptic dopamine. Reduce. Recent studies have shown that 5-HT _2C agonists are prefrontal cortex and nucleus accumbens, (Millan, MJ, et al., Neuropharmacology, 37: 953-955, 1998; Di Matteo, V , et al., Neuropharmacology 38: 1195-1205, 1999; Di Giovanni, G., et al., Synapse 35: 53-61, 2000), which is thought to mediate the critical antipsychotic effects of drugs such as clozapine Proved to reduce the level of dopamine in the brain area. In contrast, 5-HT _2C agonists do not reduce dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects. In addition, recent studies have demonstrated that 5-HT _2C agonists reduce firing in the ventral tegmental area (VTA) but not in the substantia nigra. ing. The different effects of 5-HT _2C agonists on the mesolimbic pathway on the nigrostriatal pathway indicate that 5-HT _2C agonists have limbic selectivity and are associated with typical antipsychotics This suggests that it is less likely to cause extrapyramidal side effects.

Atypical antipsychotics bind to 5-HT _2C receptors with high affinity and function as 5-HT _2C receptor antagonists or inverse agonists. Weight gain is a troublesome side effect associated with atypical antipsychotics such as clozapine and olanzapine, and 5-HT _2C antagonism has been suggested to be responsible for increased weight gain. Conversely, stimulation of 5-HT _2C receptors is known to result in food intake and weight loss (Walsh et al., Psychopharmacology, 124: 57-73, 1996; Cowen, PJ, et al., Human Psychopharmacology, 10: 385-391, 1995; Rosenzweig-Lipson, S., et al., ASPET abstract, 2000). As a result, 5-HT _2C agonists and partial agonists are less likely to cause weight gain associated with current atypical antipsychotics. Indeed, 5-HT _2C agonists and partial agonists are characterized by obesity, ie excess body fat or adipose tissue, and for example type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, It is very advantageous for the treatment of medical illnesses associated with comorbidities such as sleep apnea, gallbladder disease, gout, some cancers, some infertility, and premature death.

は、有力な５−ＨＴ_2Cアゴニストである。２００３年４月２４日出願の米国特許出願第１０／４２２，５２４号および国際出願第ＷＯ ０３／０９１２５０号参照。これらの各々は、その全体が参照して本明細書に組み込まれる。化合物Ａはまた、統合失調症に関連した気分障害または認知障害の治療においても効果的でありうる。 Compound (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline Hydrochloride (Compound A / HCl)

Is a potent 5-HT _2C agonist. See US patent application Ser. No. 10 / 422,524 filed Apr. 24, 2003 and International Application No. WO 03/091250. Each of these is hereby incorporated by reference in its entirety. Compound A may also be effective in treating mood disorders or cognitive disorders associated with schizophrenia.

  Given the importance of compounds such as Compound A as pharmaceuticals, it can be seen that effective formulations for their delivery are very important. The present invention is directed to these important objectives as well as other important objectives.

  In one embodiment, the invention provides a compound of formula I as described herein, preferably (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12, Provided is a pharmaceutical composition comprising 12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydrochloride (Compound A · HCl) in enteric coated form. In a further embodiment, the invention provides such a composition further comprising a sustained release component that may include one or more controlled release excipients.

（式中：
Ｒ¹は、水素、１〜６炭素原子のアルキル、２〜６炭素原子のアルカノイル、または７〜１１炭素原子のカルボアリールアルコキシであり；
Ｒ²およびＲ³は各々独立して、水素、ヒドロキシ、１〜６炭素原子のアルキル、１〜６炭素原子のアルコキシ、ハロゲン、カルボキサミド、２〜６炭素原子のカルボアルコキシ、１〜６炭素原子のペルフルオロアルキル、シアノ、１〜６炭素原子のアルカンスルホンアミド、１〜６炭素原子のアルカンスルホニル、１〜６炭素原子のアルカンアミド、アミノ、１〜６炭素原子のアルキルアミノ、１アルキル部分あたり１〜６炭素原子のジアルキルアミノ、１〜６炭素原子のペルフルオロアルコキシ、２〜６炭素原子のアルカノイルオキシ、２〜６炭素原子のアルカノイル、６〜８炭素原子のアロイル、５〜７炭素原子のアリール、アリール部分に５〜７炭素原子を有するＣ₆〜Ｃ₁₃アルキルアリール基、５〜７員ヘテロアリール基、またはヘテロアリール部分に５〜７員を有する、６〜１３員アルキルヘテロアリール基であり、ここで、アリールまたはヘテロアリール部分を有するあらゆるＲ²またはＲ³置換基は場合により、アリールまたはヘテロアリール部分上で、ハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、またはＣ₁〜Ｃ₆アルコキシ基から独立して選択された１〜３置換基で置換されてもよく；
Ｒ⁴およびＲ⁵は独立して、水素または１〜６炭素原子のアルキルであるか、またはＲ⁴およびＲ⁵は、これらが付着している炭素とともに、４〜８炭素原子のシクロアルカン、４〜８炭素原子のシクロアルケン、５〜１０炭素原子の架橋二環式アルカン、５〜１０炭素原子の架橋二環式アルケン、硫黄原子が場合によりスルホキシドもしくはスルホンへ酸化されているピランもしくはチオピランを形成し、ここで、Ｒ⁴およびＲ⁵によって形成された環状部分は場合により、ハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、またはＣ₁〜Ｃ₆アルコキシ基から独立して選択された１〜３置換基で置換されてもよく；
Ｒ⁶およびＲ⁷は各々独立して、水素または１〜６炭素原子のアルキルであり；
ｎは１または２であり；そして
破線は、任意二重結合を表わす）または
医薬的に許容し得るその塩
を有する医薬組成物を提供する。 In some embodiments, the present invention is a pharmaceutical composition comprising:
a) a pharmaceutically effective amount of active drug comprising about 10 to about 80% by weight of the pharmaceutical composition;
b) a filler component comprising about 10 to about 80% by weight of the pharmaceutical composition;
c) an optional seal coat component comprising about 0.01 to about 5% by weight of the pharmaceutical composition;
d) an enteric coat component comprising about 0.01 to about 20% by weight of the pharmaceutical composition;
e) optional glidant component comprising about 0.01 to about 20% by weight of the pharmaceutical composition;
f) Optional plasticizer component comprising about 0.01 to about 3% by weight of the pharmaceutical composition;
g) an optional neutralizer component comprising about 0.01 to about 1.5% by weight of the pharmaceutical composition;
h) any surfactant component comprising about 0.001 to about 1.0% by weight of the pharmaceutical composition;
i) an optional lubricant component comprising about 0.01 to about 5.0% by weight of the pharmaceutical composition, wherein the active drug is of formula I:

(Where:
R ¹ is hydrogen, alkyl of 1-6 carbon atoms, alkanoyl of 2-6 carbon atoms, or carboarylalkoxy of 7-11 carbon atoms;
R ² and R ³ are each independently hydrogen, hydroxy, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, carboxamide, carboalkoxy of 2-6 carbon atoms, 1-6 carbon atoms Perfluoroalkyl, cyano, 1-6 carbon atom alkanesulfonamide, 1-6 carbon atom alkanesulfonyl, 1-6 carbon atom alkaneamide, amino, 1-6 carbon atom alkylamino, 1 per alkyl moiety 6 carbon atoms dialkylamino, 1-6 carbon atoms perfluoroalkoxy, 2-6 carbon atoms alkanoyloxy, 2-6 carbon atoms alkanoyl, 6-8 carbon atoms aroyl, 5-7 carbon atoms aryl, aryl C ₆ -C ₁₃ alkylaryl group having 5 to 7 carbon atoms in the moiety, 5- to 7-membered heteroaryl group or f, A 6-13 membered alkylheteroaryl group having 5-7 members in the teloaryl moiety, wherein any R ² or R ³ substituent having an aryl or heteroaryl moiety is optionally on the aryl or heteroaryl moiety , halogen atom, C ₁ -C ₆ alkyl or C ₁ -C ₆ may be substituted with 1-3 substituents independently selected from alkoxy groups;
R ⁴ and R ⁵ are independently hydrogen or alkyl of 1 to 6 carbon atoms, or R ⁴ and R ⁵ together with the carbon to which they are attached, a 4 to 8 carbon atom cycloalkane, 4 A cycloalkene of ˜8 carbon atoms, a bridged bicyclic alkane of 5-10 carbon atoms, a bridged bicyclic alkene of 5-10 carbon atoms, forming a pyran or thiopyran in which the sulfur atom is optionally oxidized to a sulfoxide or sulfone Wherein the cyclic moiety formed by R ⁴ and R ⁵ is optionally 1-3 substituted independently selected from halogen atoms, C ₁ -C ₆ alkyl groups, or C ₁ -C ₆ alkoxy groups May be substituted with a group;
R ⁶ and R ⁷ are each independently hydrogen or alkyl of 1 to 6 carbon atoms;
n is 1 or 2; and the dashed line represents an optional double bond) or a pharmaceutical composition having a pharmaceutically acceptable salt thereof.

In some embodiments, R ² is hydrogen, halogen, cyano, perfluoroalkyl of 1 to 3 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, Alkanesulfonyl of 1-6 carbon atoms or aryl of 5-7 carbon atoms. In some further embodiments, R ² is hydrogen, halogen, cyano, alkoxy of 1 to 3 carbon atoms, phenyl, or trifluoromethyl. In still further embodiments, R ³ is hydrogen, halogen, cyano, perfluoroalkyl of 1-3 carbon atoms, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkanoyl of 2-6 carbon atoms, 1 Alkanesulfonyl of -6 carbon atoms or aryl of 5-7 carbon atoms.

In some further embodiments, R ³ is hydrogen, halogen, cyano, alkoxy of 1 to 3 carbon atoms, phenyl, or trifluoromethyl. In a further embodiment, R ⁴ and R ⁵ preferably together with the carbon atom to which they are attached form a 5-8 carbon atom cycloalkane or cycloalkene moiety, wherein one of these carbon atoms or More than that is optionally substituted by alkyl of 1 to 4 carbon atoms. In still further embodiments, R ⁴ and R ⁵ preferably together with the carbon atom to which they are attached form a cycloalkane moiety of 5-7 carbon atoms. In some embodiments, R ⁶ and R ⁷ are each hydrogen. In a further embodiment, n is 1. In some further embodiments, R ² and R ³ are independently selected from hydrogen, halo, trifluoromethyl, phenyl, or alkoxy of 1 to 3 carbon atoms, and R ¹ , R ⁶ , and R ⁷ are Each is hydrogen, n is 1, and R ⁴ and R ⁵ together with the carbon atom to which they are attached form cyclopentane, cyclohexane, or cycloheptane. In some particularly preferred embodiments, the active drug is Compound A, or a pharmaceutically acceptable salt thereof, preferably Compound A · HCl.

In some embodiments,
The active drug comprises about 15 to about 25%, or about 20 to about 22%, or about 20 to about 40%, or about 30 to about 40% by weight of the pharmaceutical composition;

  The filler component comprises about 50 to about 70%, or about 60 to about 66%, or about 40 to about 70%, or about 40 to about 50% by weight of the pharmaceutical composition;

  When present, the optional seal coat component is about 0.5 to about 3%, or about 1 to about 3%, or about 1 to about 2%, or about 2 to about 3% by weight of the pharmaceutical composition. Comprising:

  The enteric coat component is about 5 to about 15%, or about 8 to about 12%, or about 12 to about 16%, or about 8 to about 16%, or about 9 to about% by weight of the pharmaceutical composition. 11% by weight, or about 9.6 to about 10.6% by weight, or about 10.0 to about 10.2% by weight;

  When present, the optional glidant component comprises about 0.01 to about 1%, or about 0.1 to about 0.3%, or about 0.1 to about 3% by weight of the pharmaceutical composition And

  When present, the optional plasticizer component is about 0.1 to about 1.5%, or about 0.5 to about 1.0%, or about 0.5 to about 2.0% by weight of the pharmaceutical composition. % Comprises;

  When present, the optional neutralizer component is about 0.01 to about 0.8%, or about 0.05 to about 0.3%, or about 0.03 to about 0.3% by weight of the pharmaceutical composition. Constitutes% by weight;

  When present in the optional surfactant component, about 0.005 to about 0.05% by weight of the pharmaceutical composition, or about 0.005 to about 0.025% by weight, or about 0.001 to about 0.3%. Constitutes% by weight;

  When the optional lubricant component is present, it constitutes about 1 to about 4%, or about 2.5 to about 3.5%, or about 2 to about 3.5% by weight of the pharmaceutical composition.

In some further embodiments,
a) The active drug is about 30 to about 80% by weight of the pharmaceutical composition, or about 30 to about 45% by weight of the pharmaceutical composition, or about 50 to about 70% by weight of the pharmaceutical composition, or about Comprises 60 to about 70% by weight;
b) the filler component comprises about 40 to about 60% by weight of the pharmaceutical composition, or about 10 to about 30% by weight of the pharmaceutical composition;
c) comprises from about 0.5 to about 3% by weight of the pharmaceutical composition when optional seal coat ingredients are present;
d) the enteric coat component comprises from about 5 to about 15% by weight of the pharmaceutical composition;
e) comprises from about 0.1 to about 2% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.1 to about 1.5% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.01 to about 0.8% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) comprises from about 0.005 to about 0.05% by weight of the pharmaceutical composition when optional surfactant component is present;
i) constitutes from about 1 to about 4% by weight of the pharmaceutical composition when the optional lubricant component is present;

  In some embodiments, a glidant component, a plasticizer component, a neutralizer component, a surfactant component, and a lubricant component are each present in the formulation.

  In some embodiments, the filler component comprises microcrystalline cellulose, lactose, starch, carboxymethylcellulose, cellulose gum, polyethylene glycol, substituted cellulose, ethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, calcium phosphate, anhydrous dicalcium phosphate, metal One or more of aluminosilicate, magnesium aluminometasilicate (eg Neusilin®), sugar or carbohydrate containing compound, mannitol, sucrose, maltodextrin, sorbitol, starch, xylitol, metal phosphate, metal carbonate, and magnesium carbonate Including more. In some preferred embodiments, the filler comprises microcrystalline cellulose.

  In some embodiments, when optional seal coat components are present, Opadry® II clear, other Opadry® coat materials, Kollicoat® maltodextrin, Pure-Cote® , Pharmacoat®, or other cellulose- or starch-basecoat.

  In some embodiments, the enteric coat component is a methacrylate copolymer, wherein the copolymer is anionic, such as Eudragit® L30D-55 dry polymer, or cationic, such as Eudragit® aminoalkyl. A methacrylate copolymer that has functional groups at pH, or that the copolymer has no functional groups, i.e., is pH-independent and therefore neutral, such as Eudragit® NE30D / 40D; methacrylic acid copolymers, such as Acryl-EZE®; HPMC-containing enteric coating systems, such as Spectrablend ™; CAP; HPMCP; acrylic polymers, such as Eastacryl ( Mark), or other acrylate -, methacrylate - or cellulose acetate phthalate, - comprises one or more of the base coat. In some preferred embodiments, the enteric coat component comprises Eudragit® L30D-55 dry polymer. In such embodiments, the copolymer, polymer, or coating system may be in various forms such as granules, solid materials, dispersions, or organic solutions.

  In some embodiments, when any glidant component is present, mono- and di-glycerides, talc, silicon dioxide, stearic acid, starch, powdered cellulose, lactose, stearate, calcium phosphate, magnesium carbonate, Contains one or more of magnesium oxide, silicate, and silicon dioxide aerogel. In some preferred embodiments, the glidant comprises mono- and di-glycerides, such as Imwitor® 900K.

  In some embodiments, when any plasticizer component is present, triethyl citrate, dibutyl sebecate, polyethylene glycol, propylene glycol, triacetin, sorbitol, tributyl citrate, acetyl tributyl citrate, acetyl triethyl Contains one or more of citrate, dibutyl phthalate, triethyl citrate, and triethanolamine. In some preferred embodiments, the plasticizer component comprises triethyl citrate.

In some embodiments, when any neutralizer component is present, it comprises one or more of NaOH, KOH, and NH ₄ OH. In some preferred embodiments, the plasticizer component comprises NaOH.

  In some embodiments, when optional surfactant components are present, polysorbate 80, sodium lauryl sulfate, sucrose palmitate, poloxamer, sodium doxate, and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, It includes one or more of sucrose fatty acid esters and sorbitan fatty acid esters. In some preferred embodiments, the surfactant component comprises polysorbate 80.

  In some embodiments, when any lubricant component is present, talc, metal stearate, silicon dioxide, sodium stearyl fumarate, fatty acid ester, fatty acid, fatty alcohol, glyceryl behenate, mineral oil, paraffin, hydrogenation Contains one or more of vegetable oil, leucine, polyethylene glycol, metal lauryl sulfate, silica, eg Aerosil® 200, and sodium chloride. In some preferred embodiments, the lubricant component comprises talc.

  In some embodiments, the active drug comprises Compound A, or a pharmaceutically acceptable salt thereof, preferably Compound A · HCl, the filler component comprises microcrystalline cellulose; Opadry® II clear included; enteric coat component includes Eudragit® L30D-55 dry polymer; glidant component includes mono- and di-glycerides; plasticizer component includes triethyl The neutralizer component includes NaOH; the surfactant component includes polysorbate 80; the lubricant component includes talc.

  In some embodiments of each of the compositions, the composition comprises a plurality of enteric coated pellets. In some such embodiments, these enteric coated pellets are present in a capsule.

The present invention is further a method for preparing the disclosed pharmaceutical composition comprising:
a) preparing uncoated pellets containing the filler and the active drug;
b) optionally providing a method comprising adding a subcoat to these uncoated pellets; and c) adding an enteric coating to these pellets.
In some embodiments, the method further comprises:
d) also including the step of filling capsules with said pellets to obtain a predetermined dose of Compound A, or a pharmaceutically acceptable salt thereof, preferably Compound A.HCl.

In some embodiments, step (a) comprises
i) mixing the filler and the active drug to form a mixture;
ii) wet granulating the mixture to form granules; and iii) extruding the granules to spheronize.

In some embodiments, step (c) comprises
i) a step of preparing a suspension comprising the enteric coat, the plasticizer, the neutralizing agent, and the surfactant;
ii) spraying the suspension onto the pellets.

  The present invention also provides the products of the methods described herein.

In some embodiments, the present invention provides a pharmaceutical composition comprising a plurality of enteric coated pellets, wherein the pellet comprises a) about 20 to about 22% by weight of the pharmaceutical composition;
b) a filler component comprising about 60 to about 66% by weight of the pharmaceutical composition;
c) optional sealcoat component, if present, comprising about 1 to about 2% by weight of the pharmaceutical composition;
d) an enteric coat component comprising about 8 to about 12% by weight of the pharmaceutical composition;
e) any glidant component that, if present, comprises from about 0.1 to about 0.3% by weight of the pharmaceutical composition;
f) any plasticizer component that, if present, comprises from about 0.5 to about 1.0% by weight of the pharmaceutical composition;
g) any neutralizer component that, when present, comprises from about 0.05 to about 0.3% by weight of the pharmaceutical composition;
h) any surfactant component that, when present, comprises about 0.005 to about 0.025% by weight of the pharmaceutical composition;
i) if present, includes any lubricant component comprising about 2.5 to about 3.5% by weight of the pharmaceutical composition;
The active drug comprises Compound A, or a pharmaceutically acceptable salt thereof, preferably Compound A.HCl;
The filler component comprises microcrystalline cellulose;
Including Opadry® II clear when a seal coat component is present;
The enteric coat component comprises a methacrylic copolymer, such as Eudragit® L30D-55;
When a glidant component is present, including mono- and di-glycerides;
Including triethyl citrate when a plasticizer component is present;
Including NaOH when a neutralizer component is present;
When the surfactant component is present, including polysorbate 80; and when the lubricant component is present, including talc,
A pharmaceutical composition is provided.
including.

  In some embodiments, each of the components (c), (e), (f), (g), (h), and (i) is present.

  In some embodiments of each of the pharmaceutical compositions and methods, the composition comprises about 0.5 mg to about 5.0 mg of active drug, or about 1.0 mg to about 3.0 mg of active drug, or about 1.5 mg to about 2.5 mg active drug, or about 20 mg to about 30 mg active drug, or about 22.5 mg to about 27.5 mg active drug, or about 24.0 mg to about 26.0 mg active drug, Or about 50 mg to about 100 mg active drug, or about 65 mg to about 85 mg active drug, or about 70 mg to about 80 mg active drug, or about 75 mg to about 125 mg active drug, or about 90 mg to about 110 mg active drug, Or about 72 mg to about 76 mg of active drug, or about 20 mg to about 110 mg of active drug.

  In some further embodiments, the composition comprises from about 50.0 mg to about 750.0 mg active drug, or from about 50.0 mg to about 200.0 mg active drug, or from about 100.0 mg to about 175.0 mg. Of active drug, or about 125.0 mg to about 175.0 mg of active drug.

  In some further embodiments, the composition comprises from about 100.0 mg to about 750.0 mg active drug, or from about 150.0 mg to about 750.0 mg active drug, or from about 200.0 mg to about 750.0 mg. Of active drug, or about 300.0 mg to about 750.0 mg of active drug. In some embodiments, the composition comprises about 2 mg, about 4 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg. About 600 mg, about 700 mg, or about 750 mg of active drug.

  In some embodiments of each of the pharmaceutical compositions described herein, the composition may further comprise a sustained release component. In some embodiments, the sustained release component is a coating disposed between an optional seal coat component and an enteric coat component. In some embodiments, the sustained release coating comprises a controlled release excipient such as gelatin, shellac, hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), ethylcellulose (EC), hydroxypropylmethylcellulose phthalate (HPMCP), Contains one or more of cellulose acetate phthalate (CAP), methacrylic acid / methyl methacrylate copolymer, polyvinyl acetate phthalate (PVAP), glyceryl behenate, paraffin, or carnauba wax.

  During initial toxicity testing, dogs were found to have an emetic response to Compound A.HCl when given as an oral suspension. Capsules with an enteric coating have been developed that delay the release of this drug. This formulation has been found to improve tolerability and allow higher dosages in toxicity studies with dogs. For human clinical studies, enteric-coated pellets have been developed that offer superior advantages over enteric-coated capsules for dose flexibility and more uniform release in the intestinal tract.

  Thus, the present invention provides a pharmaceutical composition comprising a [1,4] diazepino [6,7,1-ij] quinoline derivative, and in particular antipsychotic and obesity-suppressing compound A, or pharmaceutically acceptable. The resulting salt, preferably compound A.HCl, is provided. In some preferred embodiments, the compositions of the invention are delayed release formulations. In some such embodiments, delayed release is achieved using an enteric coating. In some embodiments, the composition comprises enteric coated pellets.

（式中：
Ｒ¹は、水素、１〜６炭素原子のアルキル、２〜６炭素原子のアルカノイル、または７〜１１炭素原子のカルボアリールアルコキシであり；
Ｒ²およびＲ³は各々独立して、水素、ヒドロキシ、１〜６炭素原子のアルキル、１〜６炭素原子のアルコキシ、ハロゲン、カルボキサミド、２〜６炭素原子のカルボアルコキシ、１〜６炭素原子のペルフルオロアルキル、シアノ、１〜６炭素原子のアルカンスルホンアミド、１〜６炭素原子のアルカンスルホニル、１〜６炭素原子のアルカンアミド、アミノ、１〜６炭素原子のアルキルアミノ、１アルキル部分あたり１〜６炭素原子のジアルキルアミノ、１〜６炭素原子のペルフルオロアルコキシ、２〜６炭素原子のアルカノイルオキシ、２〜６炭素原子のアルカノイル、６〜８炭素原子のアロイル、５〜７炭素原子のアリール、アリール部分に５〜７炭素原子を有するＣ₆〜Ｃ₁₃アルキルアリール基、５〜７員ヘテロアリール基、またはヘテロアリール部分に５〜７員を有する、６〜１３員アルキルヘテロアリール基であり、ここで、アリールまたはヘテロアリール部分を有するいずれのＲ²またはＲ³置換基も場合により、アリールまたはヘテロアリール部分上で、ハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、またはＣ₁〜Ｃ₆アルコキシ基から独立して選択された１〜３置換基で置換されてもよく；
Ｒ⁴およびＲ⁵は独立して、水素または１〜６炭素原子のアルキルであるか、またはＲ⁴およびＲ⁵は、これらが付着している炭素とともに、４〜８炭素原子のシクロアルカン、４〜８炭素原子のシクロアルケン、５〜１０炭素原子の架橋二環式アルカン、５〜１０炭素原子の架橋二環式アルケン、硫黄原子が場合によりスルホキシドもしくはスルホンへ酸化されているピランもしくはチオピランから選択される環状部分を形成し、ここで、Ｒ⁴およびＲ⁵によって形成された環状部分は場合により、ハロゲン原子、Ｃ₁〜Ｃ₆アルキル基、またはＣ₁〜Ｃ₆アルコキシ基から独立して選択された１〜３置換基で置換されてもよく；
Ｒ⁶およびＲ⁷は各々独立して、水素または１〜６炭素原子のアルキルであり；
ｎは１または２であり；そして
破線は、任意二重結合を表わす）または、
医薬的に許容し得るその塩
を有する医薬組成物を提供する。 In one embodiment, the present invention is a pharmaceutical composition comprising:
a) a pharmaceutically effective amount of active drug comprising about 10 to about 80% by weight of the pharmaceutical composition;
b) a filler component comprising about 10 to about 80% by weight of the pharmaceutical composition;
c) an optional seal coat component comprising about 0.01 to about 5% by weight of the pharmaceutical composition;
d) an enteric coat component comprising about 0.01 to about 20% by weight of the pharmaceutical composition;
e) optional glidant component comprising about 0.01 to about 20% by weight of the pharmaceutical composition;
f) Optional plasticizer component comprising about 0.01 to about 3% by weight of the pharmaceutical composition;
g) an optional neutralizer component comprising about 0.01 to about 1.5% by weight of the pharmaceutical composition;
h) any surfactant component comprising about 0.001 to about 1.0% by weight of the pharmaceutical composition;
i) an optional lubricant component comprising about 0.01 to about 5.0% by weight of the pharmaceutical composition, wherein the active drug is of formula I:

(Where:
R ¹ is hydrogen, alkyl of 1-6 carbon atoms, alkanoyl of 2-6 carbon atoms, or carboarylalkoxy of 7-11 carbon atoms;
R ² and R ³ are each independently hydrogen, hydroxy, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, carboxamide, carboalkoxy of 2-6 carbon atoms, 1-6 carbon atoms Perfluoroalkyl, cyano, 1-6 carbon atom alkanesulfonamide, 1-6 carbon atom alkanesulfonyl, 1-6 carbon atom alkaneamide, amino, 1-6 carbon atom alkylamino, 1 per alkyl moiety 6 carbon atoms dialkylamino, 1-6 carbon atoms perfluoroalkoxy, 2-6 carbon atoms alkanoyloxy, 2-6 carbon atoms alkanoyl, 6-8 carbon atoms aroyl, 5-7 carbon atoms aryl, aryl C ₆ -C ₁₃ alkylaryl group having 5 to 7 carbon atoms in the moiety, 5- to 7-membered heteroaryl group or f, A 6-13 membered alkylheteroaryl group having 5-7 members in the teloaryl moiety, wherein any R ² or R ³ substituent having an aryl or heteroaryl moiety is optionally on the aryl or heteroaryl moiety in, a halogen atom, C ₁ -C ₆ alkyl or C ₁ -C ₆ may be substituted with 1-3 substituents independently selected from alkoxy groups;
R ⁴ and R ⁵ are independently hydrogen or alkyl of 1 to 6 carbon atoms, or R ⁴ and R ⁵ together with the carbon to which they are attached, a 4 to 8 carbon atom cycloalkane, 4 Selected from cycloalkenes of ˜8 carbon atoms, bridged bicyclic alkanes of 5-10 carbon atoms, bridged bicyclic alkenes of 5-10 carbon atoms, pyran or thiopyran, in which the sulfur atom is optionally oxidized to sulfoxide or sulfone Wherein the cyclic moiety formed by R ⁴ and R ⁵ is optionally independently selected from a halogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkoxy group Optionally substituted with 1 to 3 substituents;
R ⁶ and R ⁷ are each independently hydrogen or alkyl of 1 to 6 carbon atoms;
n is 1 or 2; and the dashed line represents an optional double bond) or
A pharmaceutical composition having a pharmaceutically acceptable salt thereof is provided.

In some embodiments, R ² is hydrogen, halogen, cyano, perfluoroalkyl of 1 to 3 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, Alkanesulfonyl of 1-6 carbon atoms or aryl of 5-7 carbon atoms. In some further embodiments, R ² is hydrogen, halogen, cyano, alkoxy of 1 to 3 carbon atoms, phenyl, or trifluoromethyl. In still further embodiments, R ³ is hydrogen, halogen, cyano, perfluoroalkyl of 1-3 carbon atoms, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkanoyl of 2-6 carbon atoms, 1 Alkanesulfonyl of -6 carbon atoms or aryl of 5-7 carbon atoms.

In some further embodiments, R ³ is hydrogen, halogen, cyano, alkoxy of 1 to 3 carbon atoms, phenyl, or trifluoromethyl. In a further embodiment, R ⁴ and R ⁵ preferably together with the carbon atom to which they are attached form a 5-8 carbon atom cycloalkane or cycloalkene moiety, wherein one of these carbon atoms or More is optionally substituted by alkyl of 1 to 4 carbon atoms. In still further embodiments, R ⁴ and R ⁵ preferably together with the carbon atom to which they are attached form a cycloalkane moiety of 5-7 carbon atoms. In some embodiments, R ⁶ and R ⁷ are each hydrogen. In a further embodiment, n is 1. In some further embodiments, R ² and R ³ are independently selected from hydrogen, halo, trifluoromethyl, phenyl, or alkoxy of 1 to 3 carbon atoms, and R ¹ , R ⁶ , and R ⁷ are Each is hydrogen, n is 1, and R ⁴ and R ⁵ together with the carbon atom to which they are attached form cyclopentane, cyclohexane, or cycloheptane.

  In some particularly preferred embodiments, the active drug is Compound A · HCl.

In some embodiments,
The active drug comprises about 15 to about 25%, or about 20 to about 22%, or about 20 to about 40%, or about 30 to about 40% by weight of the pharmaceutical composition;
The filler component comprises about 50 to about 70%, or about 60 to about 66%, or about 40 to about 70%, or about 40 to about 50% by weight of the pharmaceutical composition;
When present, the optional seal coat component is about 0.5 to about 3%, or about 1 to about 3%, or about 1 to about 2%, or about 2 to about 3% by weight of the pharmaceutical composition. Comprising:
The enteric coat component is about 5 to about 15%, or about 8 to about 12%, or about 12 to about 16%, or about 8 to about 16%, or about 9 to about% by weight of the pharmaceutical composition. 11% by weight, or about 9.6 to about 10.6% by weight, or about 10.0 to about 10.2% by weight;
When present, the optional glidant component comprises about 0.01 to about 1%, or about 0.1 to about 0.3%, or about 0.1 to about 3% by weight of the pharmaceutical composition And
When present, the optional plasticizer component is about 0.1 to about 1.5%, or about 0.5 to about 1.0%, or about 0.5 to about 2.0% by weight of the pharmaceutical composition. % Comprises;
When present, the optional neutralizer component is about 0.01 to about 0.8%, or about 0.05 to about 0.3%, or about 0.03 to about 0.3% by weight of the pharmaceutical composition. Constitutes% by weight;
When present in the optional surfactant component, about 0.005 to about 0.05% by weight of the pharmaceutical composition, or about 0.005 to about 0.025% by weight, or about 0.001 to about 0.3%. From about 1 to about 4%, or from about 2.5 to about 3.5%, or from about 2.0 to about 3% by weight of the pharmaceutical composition when optional lubricant components are present Constitutes 5% by weight.

In some further embodiments,
a) The active drug is about 30 to about 80% by weight of the pharmaceutical composition, or about 30 to about 45% by weight of the pharmaceutical composition, or about 50 to about 70% by weight of the pharmaceutical composition, or about Comprises 60 to about 70% by weight;
b) the filler component comprises about 40 to about 60% by weight of the pharmaceutical composition, or about 10 to about 30% by weight of the pharmaceutical composition;
c) comprises from about 0.5 to about 3% by weight of the pharmaceutical composition when optional seal coat ingredients are present;
d) the enteric coat component comprises from about 5 to about 15% by weight of the pharmaceutical composition;
e) comprises from about 0.1 to about 2% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.1 to about 1.5% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.01 to about 0.8% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) comprises about 0.005 to about 0.05% by weight of the pharmaceutical composition when optional surfactant component is present; and i) about of the pharmaceutical composition when optional lubricant component is present 1 to about 4% by weight.

  In some embodiments, a glidant component, a plasticizer component, a neutralizer component, a surfactant component, and a lubricant component are each present in the formulation.

  In some embodiments of the pharmaceutical compositions and methods described herein, the composition comprises from about 0.5 mg to about 5.0 mg of active drug, or from about 1.0 mg to about 3.0 mg. Active drug, or about 1.5 mg to about 2.5 mg active drug, or about 20 mg to about 30 mg active drug, or about 22.5 mg to about 27.5 mg active drug, or about 24.0 mg to about 26. 0 mg active drug, or about 50 mg to about 100 mg active drug, or about 65 mg to about 85 mg active drug, or about 70 mg to about 80 mg active drug, or about 75 mg to about 125 mg active drug, or about 90 mg to about Contains 110 mg of active drug, or about 72 mg to about 76 mg of active drug.

  In some further embodiments, the composition comprises from about 50.0 mg to about 750.0 mg active drug, or from about 50.0 mg to about 200.0 mg active drug, or from about 100.0 mg to about 175.0 mg. Of active drug, or about 125.0 mg to about 175.0 mg of active drug.

  In some further embodiments, the composition comprises from about 100.0 mg to about 750.0 mg active drug, or from about 150.0 mg to about 750.0 mg active drug, or from about 200.0 mg to about 750.0 mg. Of active drug, or about 300.0 mg to about 750.0 mg of active drug. In some embodiments, the composition comprises about 2 mg, about 4 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg. About 600 mg, about 700 mg, or about 750 mg of active drug.

  In some embodiments of each of the compositions, the composition comprises a plurality of enteric coated pellets. In some such embodiments, these enteric coated pellets are present in a capsule.

The present invention is further a method for preparing the disclosed pharmaceutical composition comprising:
a) preparing uncoated pellets containing the filler and the active drug;
There is also provided a method comprising b) optionally adding a subcoat to these uncoated pellets; and c) adding an enteric coating to these pellets.

In some embodiments, these methods further include:
d) also including the step of filling capsules with said pellets to obtain a predetermined dose of Compound A, or a pharmaceutically acceptable salt thereof, preferably Compound A · HCl.

In some embodiments, step (a) comprises
i) mixing the filler and the active drug to form a mixture;
ii) wet granulating the mixture to form granules; and iii) extruding the granules to spheronize.

In some embodiments, step (c) comprises
i) a step of preparing a suspension comprising the enteric coat, the plasticizer, the neutralizing agent, and the surfactant;
ii) spraying the suspension onto the pellets.

  The present invention also provides the products of the methods described herein.

In some embodiments, the present invention provides a pharmaceutical composition comprising a plurality of enteric coated pellets containing a composition described herein. In some embodiments, these pellets are
a) an active drug comprising about 20 to about 22% by weight of the pharmaceutical composition;
b) a filler component comprising about 60 to about 66% by weight of the pharmaceutical composition;
c) optional sealcoat component, if present, comprising about 1 to about 2% by weight of the pharmaceutical composition;
d) an enteric coat component comprising about 8 to about 12% by weight of the pharmaceutical composition;
e) any glidant component that, if present, comprises from about 0.1 to about 0.3% by weight of the pharmaceutical composition;
f) any plasticizer component that, if present, comprises from about 0.5 to about 1.0% by weight of the pharmaceutical composition;
g) any neutralizer component that, when present, comprises from about 0.05 to about 0.3% by weight of the pharmaceutical composition;
h) any surfactant component that, when present, comprises about 0.005 to about 0.025% by weight of the pharmaceutical composition;
i) if present, includes any lubricant component comprising about 2.5 to about 3.5% by weight of the pharmaceutical composition;
The active drug comprises Compound A, or a pharmaceutically acceptable salt thereof, preferably Compound A.HCl;
The filler component comprises microcrystalline cellulose;
Including Opadry® II clear when a seal coat component is present;
The enteric coat component includes a methacrylic copolymer, such as Eudragit® L30D-55;
When a glidant component is present, including mono- and di-glycerides;
Including triethyl citrate when a plasticizer component is present;
Including NaOH when a neutralizer component is present;
When the surfactant component is present, it includes polysorbate 80; and when the lubricant component is present, it includes talc.

  In some embodiments of the pharmaceutical composition comprising a plurality of enteric coated pellets as described above, the active drug is about 30 to about 80% by weight of the pharmaceutical composition, or about 30 to about 45% of the pharmaceutical composition. Or about 50 to about 70% by weight of the pharmaceutical composition, or about 60 to about 70% by weight of the pharmaceutical composition; the filler component is about 40 to about 60% by weight of the pharmaceutical composition, or From about 10 to about 30% by weight of the pharmaceutical composition; when present, any seal coat component comprises from about 0.5 to about 3% by weight of the pharmaceutical composition; the enteric coat component comprises the pharmaceutical composition From about 5 to about 15% by weight of the product; when present in the optional glidant component, from about 0.1 to about 2% by weight of the pharmaceutical composition; when present in the optional plasticizer component About 0.1 to about 1.5% by weight of the pharmaceutical composition; optional neutralizing agent When present, comprises from about 0.01 to about 0.8% by weight of the pharmaceutical composition; when any surfactant component is present, from about 0.005 to about 0.05% by weight of the pharmaceutical composition Constitutes about 1 to about 4% by weight of the pharmaceutical composition when the optional lubricant component is present.

  In some embodiments, each of the components (c), (e), (f), (g), (h), and (i) is present.

  In some embodiments, particularly in embodiments having less than about 30% or less than about 25% filler, it may be advantageous to further include a binder in the pellets to facilitate pellet agglomeration. is there. Any of a number of known binders for pharmaceutical formulations may be used, such as, but not limited to, HPMC and polyvinyl pyrrolidone. Further examples of suitable binders can be found, for example, in Remington's Pharmaceutical Sciences below. The binder may be present in any effective amount, for example up to about 5% by weight of the pharmaceutical composition.

  In some embodiments of each of the pharmaceutical compositions described herein, these compositions may further comprise a sustained release component. In general, the sustained release component is a coating that causes the sustained release of the active drug. In some embodiments, the sustained release coating is disposed between an optional seal coat component and an enteric coat component. Generally, the sustained release coating includes one or more controlled release excipients. Any of a wide variety of such materials known in the art are suitable. Examples of suitable controlled release excipients are gelatin, shellac, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), ethylcellulose (EC), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), methacrylic acid / Contains one or more of methyl methacrylate copolymer, polyvinyl acetate phthalate (PVAP), glyceryl behenate, paraffin, or carnauba wax. Further examples of suitable controlled release excipients can be found in Remington's Pharmaceutical Sciences above.

  It will be understood that the weight percentages shown for the components of the pharmaceutical composition described herein are the percentages in which each component constitutes the final pharmaceutical composition, regardless of the capsule. In some embodiments, the compositions of the present invention comprise or consist of enteric coated pellets. In some such embodiments, the desired dosage for the composition can be achieved by filling capsules or similar delivery vehicles with the desired amount of enteric coated pellets. In some instances where a low dosage is desired, additional fillers may be added to the enteric coated active pellets to increase the fill weight of the capsule. Any convenient filler useful in the pharmaceutical field can be used. One non-limiting example of such additional fillers are inert sugar spheres.

  Generally, the active drug or drugs may be present from about 10 to about 80% by weight of the pharmaceutical composition. In some embodiments, the active drug is about 15 to about 25% by weight of the pharmaceutical composition, or about 20 to about 22% by weight of the pharmaceutical composition, or about 30 to about 40% by weight of the pharmaceutical composition. Can exist. In some further embodiments, the active drug is about 30 to about 80% by weight of the pharmaceutical composition, or about 30 to about 45% by weight of the pharmaceutical composition, or about 50 to about 70% by weight of the pharmaceutical composition. Or about 60 to about 70% by weight of the pharmaceutical composition. In some embodiments, the active drug comprises Compound A, or a pharmaceutically acceptable salt thereof.

The filler component generally comprises about 10 to about 80%, about 50 to about 70%, or about 60 to about 66%, or about 40 to about 50% by weight of the pharmaceutical composition. In some further embodiments, the filler component comprises about 10% to about 30%, or about 10% to about 20% of the pharmaceutical composition. The filler component may include any filler compound that is useful in preparing a pharmaceutical preparation. Examples of suitable fillers are microcrystalline cellulose, lactose, starch, carboxymethyl cellulose, cellulose gum, polyethylene glycol, other substituted celluloses such as ethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, calcium phosphates such as anhydrous dicalcium phosphate, metals Of aluminosilicates such as magnesium aluminometasilicate (eg Neusilin®), sugar or carbohydrate containing compounds such as mannitol, sucrose, maltodextrin, sorbitol, starch and xylitol, and metal phosphates and carbonates such as magnesium carbonate Including one or more of them. Other suitable filler materials are, for example, ^{Remington's Pharmaceutical Sciences, 17 th ed} ., Mack Publishing Company, Easton, Pa., Can be found in 1985, which is hereby incorporated, in its entirety herein by reference. In a more preferred embodiment, the filler is microcrystalline cellulose.

  In general, the pharmaceutical compositions of the present invention are delayed release formulations. In some embodiments, delayed release is obtained by an enteric coat component (gastric resistant coating). This prevents release to the active drug down to the small intestine. Thus, in some embodiments, the enteric coat component is at a pH higher than that found in the stomach (ie, a pH greater than about 1 to about 2), and preferably release of the active drug in the small intestine. Release of the active drug at a pH suitable to produce (eg, a pH of at least about 5, such as a pH of about 5 to about 7).

  In some embodiments, a seal coat (ie, subcoat) is optionally added first, which provides a more uniform surface prior to the enteric coating. In some embodiments, the seal coat is essentially an instant release coat. That is, it does not significantly delay the release of these contents under the coating. A variety of suitable seal coats known in the art can be used. Non-limiting examples of such seal coats include Opadry® II Clear, other Opadry® coat materials (available from Colorcon), Kollicoat® (available from BASF). IR, IR white or protect grade), maltodextrin, and Pure-Cote® (available from Grain Processing Corp., Muscatine, Iowa), Pharmacoat® (Hydroxypropylmethylcellulose type polymer available from Shin-Etsu, New York, Shin-Etsu Chemical Co., Ltd.), and one or more of other cellulose- or starch-basecoats. Further examples can be found in Remington's Pharmaceutical Sciences above. In some preferred embodiments, the seal coat component comprises Opadry® II clear. Generally, when any seal coat component is present, from about 0.01 to about 5%, from about 0.5 to about 3%, or from about 1 to about 2% by weight of the pharmaceutical composition, or from about 2 to about It constitutes 3% by weight.

  Generally, the enteric coat component is about 0.01 to about 20%, or about 5 to about 15%, or about 8 to about 12%, or about 12 to about 16%, or about It comprises 9 to about 11 weight percent, or about 9.6 to about 10.6 weight percent, or about 10.0 to about 10.2 weight percent. The enteric coat component may comprise any enteric coating useful in the pharmaceutical field.

  Typically, the enteric coating contains one or more polymers that serve to impart the enteric release characteristics of the coating. Examples of suitable enteric coat components (gastric resistant coatings) include cellulose acetate phthalate (CAP) (eg Aquacoat® CPD), co-processed polyvinyl acetate phthalate (PVAP) (eg Suretetic, cellulose acetate trimellitate (CAT), methacrylic copolymers (eg Rohm America LLC of Piscataway, New Jersey, Rohm, Germany, a division of Degussa AG) Dispersion of methacrylic copolymers having an anionic functional group at pH which is a carboxylic acid, eg Eudragit® L30D-55 dry polymer from branches of GmbH & Co. KG) Liquid (30% solids), cryl-EZE® (Colorcon, West Point, Pa.), methacrylic acid copolymer type C, Eastacryl® (Eastman Chemical Company, Kingsport, Tenn.) An aqueous dispersion of an acrylic polymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and other HPMC-containing enteric coatings such as Spectrablend ™ (South Plainfield, NJ) , Sensient Pharmaceutical Technologies, South Plainfield). Further examples can be found in Remington's Pharmaceutical Sciences above. In some more preferred embodiments, the enteric coat component comprises Eudragit® L30D-55 dry polymer. In some embodiments, the coating provides an increase in enteric polymer (eg, Eudragit® L30D-55 dry polymer) of about 12% to about 22% relative to the weight of the uncoated pellets. Added to.

  Generally, when any glidant component is present, about 0.01 to about 2%, about 0.01 to about 1%, or about 0.1 to about 0.3% by weight of the pharmaceutical composition, Or about 0.1 to about 3% by weight. The glidant may be any known in the art. Non-limiting examples include mono- and di-glycerides, talc, silicon dioxide, stearic acid, starch, powdered cellulose, lactose, stearate, calcium phosphate, magnesium carbonate, magnesium oxide, silicate, and silicon dioxide aerogel. Or more. Further examples can be found in Remington's Pharmaceutical Sciences above. In some preferred embodiments, the glidant comprises mono- and di-glycerides, such as Imwitor® 900K.

  Generally, when any plasticizer component is present, about 0.01 to about 3%, about 0.1 to about 1.5%, or about 0.5 to about 1.0% by weight of the pharmaceutical composition; Or about 0.5 to about 2.0% by weight. A variety of plasticizers are useful in the compositions described herein. Non-limiting examples include triethyl citrate, dibutyl sebecate, polyethylene glycol, propylene glycol, triacetin, sorbitol, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, dibutyl phthalate, triethyl citrate, and triethyl citrate. Contains one or more of ethanolamines. Further examples of suitable plasticizers can be found in Remington's Pharmaceutical Sciences above. In some preferred embodiments, the plasticizer component comprises triethyl citrate.

Generally, when any neutralizer component is present, from about 0.01 to about 1.5%, from about 0.01 to about 0.8%, or from about 0.05 to about 0.3% by weight of the pharmaceutical composition. % Or about 0.003 to about 0.3% by weight. Any neutralizing compound suitable for the pharmaceutical field can be used. Non-limiting examples include one or more of NaOH, KOH, and NH ₄ OH. Further examples of suitable surfactants can be found in Remington's Pharmaceutical Sciences above. In some preferred embodiments, the neutralizer component comprises NaOH.

  Generally, when any surfactant component is present, about 0.001 to about 1.0%, 0.005 to about 0.05%, or about 0.005 to about 0.025% by weight of the pharmaceutical composition %, Or about 0.001 to about 0.3% by weight. A variety of surfactants known in the art can be used. Non-limiting examples include polysorbate 80, sodium lauryl sulfate, sucrose palmitate, poloxamer, sodium doxate, and one or more of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sucrose fatty acid ester, and sorbitan fatty acid ester Including more. Further examples of suitable surfactants can be found in Remington's Pharmaceutical Sciences above. In some preferred embodiments, the surfactant component comprises polysorbate 80.

  Generally, the optional lubricant component is about 0.01 to about 5.0%, about 1 to about 4%, or about 2.5 to about 3.5%, or about 2.0% by weight of the pharmaceutical composition. Constitutes about 3.5% by weight. A variety of lubricant components known in the art can be used in the composition. Non-limiting examples of suitable lubricants include talc, metal stearate, silicon dioxide, sodium stearyl fumarate, fatty acid ester, fatty acid, fatty alcohol, glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, Includes one or more of metal lauryl sulfate, silica, eg, Aerosil® 200, and sodium chloride. Further examples of suitable lubricants can be found in Remington's Pharmaceutical Sciences above. In some preferred embodiments, the glidant component comprises talc.

  The formulations described herein may include any conventionally used oral form. This includes tablets, pellets, capsules, oral forms, troches, vaginal tablets, and oral liquids, suspensions, and the like. Capsules are preferred. Capsules or tablets containing this formulation may also contain other active compounds or inert fillers and / or diluents such as pharmaceutically acceptable starches (eg corn, potato or tapioca starch), sugars, artificial sweetness It may be combined with mixtures of powders, powdered cellulose, such as crystalline and microcrystalline cellulose, wheat flour, gelatin, gums and the like. In some preferred embodiments, these formulations are contained in capsules.

  Tablet formulations can be made by conventional compression methods and utilize pharmaceutically acceptable diluents or fillers, binders, lubricants, disintegrants, suspensions or stabilizers. This includes magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, composite silicate, calcium carbonate, glycine , Dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starch, and powdered sugar, but are not limited thereto.

  Additional film coatings useful when using the formulations of the present invention are known in the art and generally consist of a polymer (usually a cellulosic polymer), a colorant, and a plasticizer. Additional ingredients such as wetting agents, sugars, flavors, oils, and lubricants may be included in the film coating formulation to impart some characteristics to the film coat. The compositions and formulations in the present invention may also be combined and processed as a solid and then placed in a capsule form, such as a gelatin capsule.

  As will be appreciated, some components of the formulations of the present invention may have multiple functions. In some such cases, the function of a given component can be considered single, even if its characteristics can allow multiple functions.

  The pharmaceutical compositions and excipient systems in the present invention may also contain an antioxidant, or a mixture of antioxidants, such as ascorbic acid. Other antioxidants that can be used include sodium ascorbate and ascorbyl palmitate, optionally with some amount of ascorbic acid. Examples of the range of one or more antioxidants are up to about 15% by weight, such as about 0.05 to about 15%, about 0.5 to about 15%, or about 0.5 to about 5% by weight. It is. In some embodiments, these pharmaceutical compositions are substantially free of antioxidants.

  A number of additional various excipients, dosage forms, dispersants, and the like suitable for use with the solid dispersions of the present invention are known in the art and described, for example, in Remington's Pharmaceutical Sciences, supra.

  In some embodiments, a pharmaceutical composition containing Compound A · HCl and a dosage form comprising the same as described herein require a therapeutically effective amount of Compound A · HCl. Supply to patient. It will be appreciated by those skilled in the art that such dosages can be provided by a single or unit dosage form of the invention or by administration of multiple such dosage forms. For example, in some embodiments, a patient is treated with a total of 24 hours of a dose of about 350 mg to about 400 mg of Compound A · HCl, preferably given in two doses of about 175 mg to about 200 mg of BID. . Such dosage may be obtained by administering a single dosage form of the invention, i.e. a dosage form containing or consisting of the composition of the invention containing the desired dose of Compound A.HCl. Can do. Alternatively, a plurality of such dosage forms can be used that together contain the desired dosage. For example, two dosage forms of the invention containing 100 mg each can be used to obtain a 200 mg dose of Compound A.HCl.

In some embodiments, the formulations of the present invention provide enteric release of the active drug, preferably Compound A.HCl. In some embodiments, the release of Compound A.HCl is effective to provide:
Human integration with an average AUCss of about 33.23 hr * ng / mL ± 20% for a dose of 100 mg Compound A · HCl, or a respective average AUC value approximately proportional to the total dose other than 100 mg In patients with schizophrenia, mean plasma concentration profile for Compound A · HCl; or about 54.88 hr * ng / mL ± 20% mean AUCss for a dose of 150 mg Compound A · HCl, or total dose other than 150 mg In human schizophrenic patients with respective mean AUC values approximately proportional to the mean plasma concentration profile for Compound A.HCl; or about 173.49 hr for a dose of 250 mg of Compound A.HCl * ng / mL ± 20% mean AUCss, or total dose other than 250 mg In human schizophrenia patients with respective mean AUC values approximately proportional to this, or mean plasma concentration profile for Compound A.HCl; or about 8.73 hr * for a dose of 25 mg of Compound A.HCl In healthy humans with a mean AUCss of ng / mL ± 20%, or a respective mean AUC value approximately proportional to total dose other than 25 mg, or mean plasma concentration profile for Compound A · HCl; or 50 mg In healthy humans having an average AUCss of about 26.49 hr * ng / mL ± 20% for the dose of Compound A · HCl, or the respective average AUC values approximately proportional to the total dose other than 50 mg , Mean plasma concentration profile for Compound A · HCl; or 75 mg of compound In healthy humans with an average AUCss of about 24.95 hr * ng / mL ± 20% for the dose of product A · HCl, or an average AUC value of each approximately proportional to the total dose other than 75 mg Mean plasma concentration profile for Compound A · HCl; or about 62.76 hr * ng / mL ± 20% mean AUCss for a dose of 100 mg Compound A · HCl, or approximately for a total dose other than 100 mg In healthy humans with respective mean AUC values proportional to this, an average plasma concentration profile for Compound A · HCl; or about 109.50 hr * ng / mL ± 20 for a dose of 150 mg of Compound A · HCl % Average AUCss, or approximately proportional to total dose other than 150 mg, respectively In healthy humans with mean AUC values; mean plasma concentration profile for Compound A · HCl; or an average AUCss of about 234.75 hr * ng / mL ± 20% for a dose of 250 mg of Compound A · HCl, or In healthy humans with respective average AUC values approximately proportional to total dose other than 250 mg, the average plasma concentration profile for Compound A · HCl; or about 4 to about in healthy humans or schizophrenic patients 6.5 hours T _max .

In some further embodiments, the invention is a unit dosage form comprising about 2 to about 150 mg of Compound _A.HCl , resulting in a C _{max of} Compound A from about 4 to about 8 hours after administration to the subject. A dosage form is provided.

  In some further embodiments, the present invention provides a unit dosage form of a drug comprising Compound A.HCl, and a degradable coating, wherein the coating is such that less than 30% of Compound A is released after 2 hours. A dosage form characterized by degrading is provided.

In some further embodiments, the invention is a unit dosage form of a medicament having a uniform dosage of Compound A.HCl, wherein Compound A.HCl is about 4 to about 8 hours after administration to a subject. Provided is a dosage form characterized by a dissolution profile upon oral administration that is released such that a C _max of Compound A occurs between. In some such embodiments, the dosage form comprises a plurality of enteric coated pellets.

In some further embodiments, the present invention is a coated extrudate comprising Compound A.HCl and a binder or filler, wherein when formulated in a unit dosage form, the C _{max of} Compound A is An extrudate is provided that achieves release of Compound A.HCl such that it occurs about 4 to about 8 hours after administration. In some such embodiments, the filler or binder comprises microcrystalline cellulose, lactose, starch, carboxymethyl cellulose, cellulose gum, polyethylene glycol, substituted cellulose, ethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, calcium phosphate, anhydrous dihydrate. Group consisting of calcium phosphate, metal aluminosilicate, magnesium aluminometasilicate (Neusilin®), sugar or carbohydrate containing compound, mannitol, sucrose, maltodextrin, sorbitol, starch, xylitol, metal phosphate, metal carbonate and magnesium carbonate And is preferably microcrystalline cellulose.

In some further embodiments, the invention provides a method for preparing a formulation comprising Compound A.HCl, comprising:
Supplying pellets comprising Compound A.HCl; and an amount that provides an enteric coating polymer weight increase of about 12% to about 22% of the enteric coating comprising the enteric coating polymer relative to the weight of the uncoated pellets. Provides a method comprising adding to these pellets.

In some further embodiments, the invention provides a method for preparing a formulation comprising Compound A.HCl, comprising:
Feeding a pellet comprising Compound A.HCl; and enteric coating (wherein Compound A.HCl is released such that C _max of Compound A occurs from about 4 to about 8 hours after administration to the subject. So that the coating degrades after administration of the formulation) to these pellets. In some such embodiments, the coating achieves a dissolution profile characterized by less than 30% release of Compound A.HCl after 2 hours.

  As discussed below, upon administration of the formulations of the present invention, a small secondary peak was seen at steady state, approximately 24-28 hours after administration. Thus, in some embodiments, the formulations of the present invention produce serum levels of Compound A · HCl characterized by a maximum peak, followed by a lower value of the secondary peak.

The “C _max ”, “T _max ”, and “AUC” values reported herein refer to the values observed in individual patients, unless stated as “average” values. To tell. Furthermore, C _max , T _max , and AUC values are steady when administered at regular time intervals (eg, every 12 hours) for multiple days (eg, multiple dose administration) unless otherwise noted. It may be the value observed in the condition or the value for a single dose administration. In some embodiments, the formulations of the present invention are for active drugs, eg, compound A · HCl that matches one or more of the dynamic parameters described below, eg, C _max , T _max , and AUC. Provides release characteristics. Such embodiments of the invention are intended to include values for these parameters that are ± 20% of the values set forth in the tables and drawings herein.

  Alkyl as used herein refers to an aliphatic hydrocarbon chain, straight and branched, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Including, but not limited to, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.

  An alkanamide as used herein refers to the group R—C (═O) —NH—, where R is an alkyl group of 1 to 5 carbon atoms.

  An alkanol as used herein refers to the group R—C (═O) —, where R is an alkyl group of 1 to 5 carbon atoms.

  Alkanoyloxy as used herein refers to the group R—C (═O) —O—, where R is an alkyl group of 1 to 5 carbon atoms.

An alkanesulfonamide, as used herein, refers to the group R—S (O) ₂ —NH—, where R is an alkyl group of 1 to 6 carbon atoms.

Alkanesulfonyl as used herein refers to the group R—S (O) ₂ —, where R is an alkyl group of 1 to 6 carbon atoms.

  Alkoxy as used herein refers to the group R—O—, where R is an alkyl group of 1 to 6 carbon atoms.

  Aryl as used herein refers to an aromatic 5-7 membered monocarbocyclic ring such as phenyl. Heteroaryl means an aromatic 5-7 membered single carbon containing a monocyclic ring having 1 or 2 heteroatoms, which may be independently nitrogen, oxygen, or sulfur.

Aroyl as used herein refers to the group Ar—C (═O) —, where Ar is aryl as defined above. For example C ₆ -C ₈ aroyl moiety, Ar-C (= O) - ( wherein, Ar is a is an aromatic 5- to 7-membered one carbocyclic ring) refers to.

  Alkylaryl as used herein is a group -R-Ar where Ar is aryl as defined above, R is 1-6, preferably 1-4, More preferably, it is an alkyl moiety having 1 to 3 carbon atoms). Examples of alkylaryl include benzyl, phenethyl, 3-phenylpropyl, and 4-phenylbutyl. An alkylheteroaryl as used herein is a group -R-hetAr where Ar is heteroaryl as defined above and R is 1-6, preferably 1 ~ 4, more preferably an alkyl moiety having 1 to 3 carbon atoms).

Carboxamide as used herein refers to the group NH ₂ —C (═O) —.

  Carboalkoxy as used herein refers to the group R—O—C (═O) —, where R is an alkyl group of 1 to 5 carbon atoms.

  A carboarylalkoxy as used herein is a group Ar—Ra—O—C (═O) —, wherein Ar is aryl as defined above, and Ra is 1 A lower alkyl group of 3 carbon atoms).

  The pharmaceutical composition of the present invention may be used for the treatment of mental disorders. This includes psychosis such as schizophrenia, schizophrenia-like disorders, schizophrenia-like disorders, paranoid disorders, substance-induced psychosis, and others, including delusional, clawed, tension, and indistinguishable L-DOPA-induced psychosis; psychosis associated with Alzheimer's dementia; psychosis associated with Parkinson's disease; psychosis associated with Lewy body disease; bipolar disorder such as type I bipolar disorder, II Type bipolar disorder and mood circulatory disorder; depressive disorder such as major depressive disorder, dysthymic disorder, substance-induced mood disorder, and other unspecified depressive disorder; mood episodes such as major depressive episodes, Manic episodes, mixed episodes, and hypomania episodes; anxiety disorders such as anxiety attacks, agoraphobia, panic disorder, specific phobia, Human fear, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, isolation anxiety disorder, substance-induced anxiety disorder, and other unspecified anxiety disorders; adaptation disorders such as anxiety and / or depression Adjustment disorders with mood; intellectual deficit disorders such as dementia, Alzheimer's disease, and memory disorders; eating disorders (eg, bulimia, bulimia, or anorexia), and combinations of these mental disorders that may be present in mammals Include. For example, mood disorders, such as depressive disorder or bipolar disorder, often occur with mental abnormalities such as schizophrenia. A more complete description of the mental disorders can be found in the "Diagnostic and Statistical Manual of Mental Disorders", 4th edition, Washington DC, American Psychiatric Association (1994). Can see.

  The pharmaceutical compositions of the present invention also include epilepsy; migraine; sexual dysfunction; sleep disorders; gastrointestinal disorders such as gastrointestinal motility dysfunction; and type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke It is also advantageous for the treatment of obesity with resulting comorbidities, including osteoarthritis, sleep apnea, gallbladder disease, gout, some cancers, some infertility, and premature death. The pharmaceutical compositions of the invention can also be used to treat central nervous system defects associated with, for example, trauma, stroke, and spinal cord injury. The pharmaceutical composition of the invention can therefore be used to ameliorate or inhibit further deterioration of central nervous system activity during or after the disease or trauma in question. These improvements also include maintaining or improving motor and motor skills, control, coordination, and strength.

  The present invention thus provides a method for the treatment of each of the diseases listed above in mammals, preferably humans, wherein a therapeutically effective amount of the pharmaceutical composition of the present invention is in need thereof. Providing a method comprising: By “treatment” as used herein is meant partial or complete alleviation, inhibition, prevention, amelioration, and / or alleviation of a disorder. For example, “treatment” as used herein includes partial or complete alleviation, inhibition or alleviation of the condition in question.

  The materials, methods, and examples presented herein are illustrative only and are not intended to limit the scope of the invention. All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety.

(Example)
As will be appreciated, the optimum amounts of the various components of the compositions disclosed herein can vary with the process parameters selected for the preparation of these compositions. The examples provided herein are not intended to limit the invention in any respect.

Preparation of Enteric Coated Capsule Containing Compound A.HCl High Dose Capsules Perform 97.75% Granulation of Compound A.HCl Containing 2% Crospovidone and 0.25% Mg Stearate Prepared by. Low strength capsules were prepared by adding lactose as a diluent. Granulation was performed by a wet granulation method. The capsules were coated in a coating pan using a Clear Opadry® subcoat followed by an aqueous dispersion of Eudragit®. This coating is used until the% increase in Eudragit® polymer is sufficient to prevent the release of this drug substance into the acid and to produce a complete release in pH 6.8 buffer after about 60 minutes. Added at a bed temperature of about 30-35 ° C. Small batches were prepared manually with solvent.

Preparation of Capsules Containing Compound A · HCl Enteric Coated Pellets These formulations consisted of spheres (pellets) containing Compound A · HCl containing a subcoat and enteric coat. Three capsule strengths were prepared from conventional stock of enteric coated pellets (approximately 20% w / w Compound A · HCl) by adjusting fill weight. In order to bring the total fill weight within the range of 25-75 mg capsule fill weight, inert sugar spheres are added to the enteric coated active pellets for 2 mg capsules.

Preparation of Compound A.HCl Enteric Coated Pellets Compound A.HCl 25% uncoated pellets were prepared by using an extrusion / spheronization method. The Compound A.HCl 25% uncoated pellets consisted of 25% Compound A.HCl chemical and 75% microcellulose (MCC). USP water was used to perform wet granulation of 25% Compound A.HCl at MCC. The following extrusion and spheronization methods were used to prepare the nuclei.

This Compound A · HCl 25% uncoated pellet was prepared according to the following procedure:
1. Microcrystalline cellulose (75%) and Compound A.HCl (25%) were mixed for 5 minutes.
2. This mixture was granulated with purified water USP to form a wet mass suitable for extrusion.
3. The granulation was extruded using a Nica ™ extruder / spheronizer with a 1.0 mm screen.
4). The extrudate was spheronized using a Nica ™ extruder / spheronizer.
The approximate spheronization time was 5 minutes.
5. These pellets were dried in a fluid bed dryer at an inlet temperature of 50 ° C. ± 5 ° C. to a moisture content of 3-4% tested at 100 ° C. in a Computrac.

The particle size distribution of each of the Compound A.HCl 25% uncoated pellets prepared by the above procedure is shown in Table 1 below.

Preparation of Compound A.HCl 20% Enteric Coated Pellets The enteric coating level of Compound A.HCl 25% pellets is selected from a variety of coating levels that provide complete protection from acids and have a minimum coating level. It was. In the enteric coating layer, 14% of the dry Eudragit® polymer weight gain can provide complete protection of the drug from acid and then release of the drug in the buffer phase, It was determined that 100% was released after 2 hours in pH 6.8 buffer.

  An in-process dissolution test was used to ensure that sufficient coating was added to these pellets to provide protection from acid dissolution and complete release in pH 6.8 buffer.

手順：
１．精製水ＵＳＰ／ＢＰ／ＥＰが、低せん断（ライトニン(Lightnin)型）または適切なミキサーを備えた適切な容器に入れられた。
２．Ｏｐａｄｒｙ（登録商標）ＩＩクリアＹ−１９−７４８３が、工程１における適度の攪拌によって、精製水ＵＳＰ／ＢＰ／ＥＰ中に生じた渦巻きへ、小さい増分で添加された。
３．工程２混合物の攪拌は、最低１時間、またはすべてのＯｐａｄｒｙ（登録商標）ＩＩクリアが溶解されるまで続行された。
４．工程３の溶液は、必要であれば、精製水ＵＳＰ／ＢＰ／ＥＰを用いて総計算重量にされた。
５．この溶液は、使用を待ちながら、室温で十分に閉鎖された容器に保存された。この溶液は、室温で保存された時、２４時間以内に用いられた。この溶液は、８４時間、２〜１０℃で保存されてもよい。 1) Subcoating of uncoated pellets Prior to adding the enteric coating layer, a subcoat was added onto the active pellets using Opadry II Clear. A subcoat was used to give a uniform surface to these pellets prior to the enteric coating. In order to give a good lubrication to the dispersion without the use of talc which tends to clog the spray nozzle and tends to be non-uniform in this dispersion, Eudragit® dispersion is glyceryl. Formulated with monostearate (Imwitter®). The following formulation was prepared:
Subcoating solution (5.0% weight / weight solids)
The 5.0% weight / weight of Opadry II Clear Y-19-7383 solution was initially used in the seal coat. A 1 kg seal coating solution preparation is shown below:

procedure:
1. Purified water USP / BP / EP was placed in a suitable container equipped with low shear (Lightnin type) or a suitable mixer.
2. Opadry® II Clear Y-19-7383 was added in small increments to the vortex produced in the purified water USP / BP / EP with moderate agitation in Step 1.
3. Stirring of the Step 2 mixture was continued for a minimum of 1 hour or until all Opadry® II clear was dissolved.
4). The solution of step 3 was brought to the total calculated weight using purified water USP / BP / EP if necessary.
5. This solution was stored in a well-closed container at room temperature while awaiting use. This solution was used within 24 hours when stored at room temperature. This solution may be stored at 2-10 ° C. for 84 hours.

For the initial sealing coating, the following coating parameters were used:

手順：
１．精製水ＵＳＰ／ＢＰ／ＥＰ、Ｉｍｗｉｔｏｒ（登録商標）９００Ｋ、トリエチルシトレート、およびツイーン８０、植物グレードが、適切なサイズのビーカーに注ぎ込まれ、磁気攪拌棒により攪拌しながら６５℃まで加熱された。
２．この混合物は、適切なホモジナイザーを用いて１５分間均質化された。
３．２０℃までの冷却後、この混合物は、ポリマー分散液へ添加された。 2) Application of enteric coat to pellets After sub-coating, a layer of about 14% enteric coating (14.81% weight / weight solids based on dry polymer weight) was added to the pellets. The coating solution formulation and coating parameters are listed below.
Preparation of enteric coating dispersion (14.81% weight / weight solids)
A. Preparation of Imwitter (R) 900K Dispersion The formulation for 200 g Imwitter (R) 900K dispersion is as follows:

procedure:
1. Purified water USP / BP / EP, Imwitter® 900K, triethyl citrate, and Tween 80, plant grade, were poured into an appropriately sized beaker and heated to 65 ° C. with stirring by a magnetic stir bar.
2. This mixture was homogenized for 15 minutes using an appropriate homogenizer.
3. After cooling to 20 ° C., the mixture was added to the polymer dispersion.

手順：
１．Ｅｕｄｒａｇｉｔ（登録商標）Ｌ３０Ｄ−５５が、低せん断（ライトニン型）または適切なミキサーを備えた適切な容器に入れられた。Ｅｕｄｒａｇｉｔ（登録商標）は、分散に先立って１８０ミクロンハンドスクリーンを通してスクリーニングされる方がよいことに留意のこと。
２．適度の攪拌をともなって、トリエチルシトレート、ＮＦ、およびＩｍｗｉｔｏｒ（登録商標）９００Ｋ分散液が、工程１懸濁液へ徐々に添加された。ついで４００．００ｇの精製水が、懸濁液へ添加され、攪拌が最低６０分間続行された。
３．水酸化ナトリウムＮＦ １Ｎ溶液が、ｐＨを５．４５に徐々に調節するために、工程２からの懸濁液へ添加された。
４．工程３懸濁液が、必要であれば精製水ＵＳＰ／ＢＰ／ＥＰで総計算重量にされ、完全に均一な混合物を得るために、最低３０分間混合された。
５．この混合物は、スプレープロセスの開始前に、４８時間まで攪拌下に室温で保存された。
６．この混合物は、使用前に１８０ミクロンハンドスクリーンを通してスクリーニングされた。 B. Preparation of Enteric Coating Suspension The following table shows the formulation for 1 kg enteric coating suspension:

procedure:
1. Eudragit® L30D-55 was placed in a suitable container equipped with a low shear (Lightnin type) or suitable mixer. Note that Eudragit® should be screened through a 180 micron hand screen prior to dispersion.
2. With moderate agitation, triethyl citrate, NF, and Imwitter® 900K dispersion were gradually added to the Step 1 suspension. 400.00 g of purified water was then added to the suspension and stirring was continued for a minimum of 60 minutes.
3. Sodium hydroxide NF 1N solution was added to the suspension from step 2 to gradually adjust the pH to 5.45.
4). Step 3 The suspension was brought to total calculated weight with purified water USP / BP / EP if necessary and mixed for a minimum of 30 minutes to obtain a completely homogeneous mixture.
5. This mixture was stored at room temperature under stirring for up to 48 hours before the start of the spray process.
6). This mixture was screened through a 180 micron hand screen prior to use.

Coating parameters for enteric coating The following shows the target coating parameters for the enteric coating process:

Formulations of Compound A.HCl 2, 25, 75, and 100 mg enteric coated pellets are shown in Table 2 below:

The functions of the excipients used in the formulation of Compound A.HCl 2, 25, 75, and 100 mg enteric coated pellets are listed in Table 3 below.

Preparation of capsules containing 75, 100, 125, and 150 mg strength Compound A.HCl enteric coated pellets The procedure of Example 2 was used. The difference was that the uncoated pellets contained 45% Compound A.HCl and 55% microcrystalline cellulose (MCC). The coating of these pellets was performed as in Example 2 (the same formulation was added to the same weight increase) but contained 1% mono- and di-glycerides. The capsule was then filled to a 150 mg dosage. If desired, the capsule can be filled to other dosages, for example 75 mg, 100 mg, or 125 mg.

Preparation of capsules containing 200, 300, 500, and 750 mg strength Compound A.HCl enteric coated pellets The procedure of Example 2 is used. The difference is that the uncoated pellets contain 80% Compound A.HCl and 20% microcrystalline cellulose (MCC). The coating of these pellets is performed as in Example 2 (same formulation added to the same weight increase) but contains 1% mono- and di-glycerides. The capsule is then filled to a dosage of 200 mg, 300 mg, 500 mg, or 750 mg.

Comparison of oral solution and enteric formulation Compound A (150 mg) was administered to 6 healthy young subjects in the form of an oral solution and as a 150 mg enteric capsule after an overnight fast of 10 hours. It was. Upon oral administration, Compound A was absorbed more rapidly from the solution compared to the enteric coated capsule formulation (150 mg, fasted). The average T _max is 2.3 hours (for average T _max = 7.0 hours for capsules). As can be seen from Figure 1, Compound A C _max, as compared to capsules, if the solution with about 1.8 times higher (for mean C _max = 7.5ng / mL vs. capsule when the solution Average C _max = 4.1 ng / mL, p <0.05). The discharge t _1/2 of Compound A was found to be about 6.6 hours. There was no significant difference in compound A AUC, CL / F, Vz / F, and t _1/2 with two different formulations (p> 0.05).

These results indicate that the _Cmax for enteric capsules is smaller, thus resulting in a reduced likelihood of GI side effects, but the bioavailability of these two formulations is comparable. In conclusion, the solution does not behave significantly differently than capsules in terms of exposure and clearance.

Administration of Enteric Coated Capsules Containing Compound A · HCl to Healthy Subjects 25, 50, 75, 100, 150, and 250 mg Compound A · HCl ascending multiple doses of 8 It was administered as a dosing regimen (q12h) twice daily for 14 days in a cohort of healthy subjects (6 active and 2 placebo). Blood samples for Compound A · HCl analysis were obtained on day 1 and 14 within 2 hours of test article administration and at various time points 0.5 to 48 hours after test article administration. . The dose was administered orally after an overnight fast of at least 10 hours over these 2 days. Trough PK samples were collected on days 7, 10, and 12 to assess whether steady state was reached.

A total of 48 subjects provided pharmacokinetic data for this analysis. After single and multiple doses, the pharmacokinetic parameters for Compound A.HCl are shown in Tables 4A and 4B, respectively. FIG. 2 shows the mean plasma concentration of Compound A · HCl versus time profile on day 1 and day 14. FIG. 3 shows the Compound A.HCl trough levels on days 7, 10, and 12 at various dose levels. 4A and 4B show the relationship between C _max versus dose and AUC versus dose, respectively.

After administration of both single and multiple doses, Compound A · HCl was absorbed from the enteric coated formulation with an average T _max of 4-6 hours. Mean excretion t _1/2 of Compound A · HCl in patients was 8-11 hours (single dose) and 6-8 hours (multiple doses).

  A small secondary peak was seen at approximately 24-28 hours on day 14 in all dose groups in the majority of subjects.

The relationship between Compound A · HCl C _max vs. dose and AUC vs. dose was described using the equation C _max or AUC = a * (dose) ^b . Compound A.HCl showed a nearly linear dose proportionality over a dose range of 25-150 mg q12h for single dose and steady state AUC and _Cmax . However, at steady state C _max and AUC, proportional slightly above than (greater-than-proportional) increase was seen at 250 mg q12h dose (an increase of about 2 ^1.4 times the AUC for the two-fold increase in dose, dose C to about ^1.3-fold increase in _max), steady state Cl / F with respect to 2-fold increase in as compared to the lower dose group was 54 to 60% lower in 250 mg q12h dose. A graphical evaluation of dose proportionality is shown in FIGS. 4A and 4B.

Administration of Enteric Coated Capsules Containing Compound A · HCl to Schizophrenia Patients Ascending multiple doses of 100, 150, and 250 mg Compound A · HCl were used in 8 schizophrenic patients (6 active And 2 placebos) for 10 days as a dosing regimen (q12h). Blood samples for Compound A.HCl analysis were obtained on day 1, within 2 hours of test article administration, and at various time points 0.5-24 hours after test article administration. On day 10, blood samples were collected by 12 hours after dose administration. The dose was administered orally after an overnight fast of at least 10 hours over these 2 days. Trough PK samples were collected on days 6, 8, and 9 to assess whether steady state was reached.

After single and multiple doses, the pharmacokinetic parameters for Compound A · HCl are shown in Tables 5A and 5B, respectively. FIG. 5 shows the mean plasma concentration of Compound A · HCl versus time profile on days 1 and 10. FIG. 6 shows the Compound A.HCl trough levels on days 6, 8, and 9 at various dose levels. Figures 7A and 7B show the relationship between _Cmax versus dose and AUC versus dose, respectively. A comparison of the steady state pharmacokinetic parameters of Compound A.HCl between healthy subjects and schizophrenic patients is shown in Table 8.

After both single and multiple dose administration to schizophrenic patients, Compound A.HCl was absorbed from the enteric coated formulation. The average T _max was 4-5 hours. Mean excretion t _1/2 of Compound A · HCl in patients was 8-10 hours after single dose administration. The excretion t _1/2 after multi-dose administration cannot be accurately assessed since samples were only collected for up to 24 hours.

The relationship between Compound A · HCl C _max vs. dose and AUC vs. dose was described using the equation C _max or AUC = a * (dose) ^b . Steady state C _max and AUC, 250 mg in q12h dose (approximately 2 ^1.6 fold increase in AUC and C _max for the two-fold increase in dose) which appeared to increase to exceed the proportionality. Deviations from 1 in exponential values were mostly caused by two patients (outliers) with very high plasma concentrations in this dose group. The relationship between dose and exposure was almost linear after these two outlier patients were excluded from the analysis. A graphical evaluation of dose proportionality is shown in FIGS. 7A and 7B. These dose proportional results were consistent with the results from healthy patients, where an increase over proportional in exposure was seen after multiple oral doses of 250 mg. Similar signs of non-linearity were also seen in a single ascending dose study after a single oral dose of 500 mg of Compound A · HCl. There was no significant difference in T _max or t _1/2 of Compound A · HCl at the 250 mg q12h dose level.

No significant difference in Compound A · HCl pharmacokinetics was found between healthy subjects and schizophrenic patients.

  Each of the patents, applications, and printed publications, including books cited in this patent document, is hereby incorporated by reference in its entirety.

  This application claims priority to US Provisional Application No. 60 / 625,280, filed Nov. 5, 2004, the entire disclosure of which is hereby incorporated by reference in its entirety. .

  As those skilled in the art will appreciate, many changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit of the invention. All such variations are intended to be within the scope of the present invention.

Figure 2 shows the Compound A mean plasma concentration versus time profile after administration of a single dose of 150 mg Compound A as a solution compared to an enteric dosage form according to the present invention. Compound A · HCl plasma concentration (mean ± SEM) versus time profile in healthy subjects receiving single and multiple (q12h) oral doses of 25, 50, 75, 100, 150, or 250 mg Compound A · HCl Show. 1 shows Compound A · HCl trough plasma concentrations in healthy subjects receiving multiple (q12h) oral doses of 25, 50, 75, 100, 150, or 250 mg Compound A · HCl. The relationship between Compound A · HCl C _max and dose in healthy young subjects receiving single and multiple (q12h) oral doses of 25, 50, 75, 100, 150, or 250 mg Compound A · HCl. Show. Shows the relationship between Compound A · HCl AUC and dose in healthy young subjects receiving single and multiple (q12h) oral doses of 25, 50, 75, 100, 150, or 250 mg Compound A · HCl. . 2 shows Compound A • HCl plasma concentration (mean ± SEM) versus time profile in schizophrenic patients receiving single and multiple (q12h) oral doses of 100, 150, or 250 mg Compound A • HCl. Figure 2 shows Compound A · HCl trough plasma concentrations in schizophrenic patients receiving multiple (q12h) oral doses of 100, 150, or 250 mg Compound A · HCl. 2 shows the relationship between Compound A · HCl C _max and dose in schizophrenic patients receiving single and multiple (q12h) oral doses of 100, 150, or 250 mg Compound A · HCl. 2 shows the relationship between Compound A · HCl AUC and dose in schizophrenic patients receiving single and multiple (q12h) oral doses of 100, 150, or 250 mg Compound A · HCl.

Claims (119)

A pharmaceutical composition comprising:
a) a pharmaceutically effective amount of active drug comprising about 10 to about 80% by weight of the pharmaceutical composition;
b) a filler component comprising about 10 to about 80% by weight of the pharmaceutical composition;
c) an optional seal coat component comprising about 0.01 to about 5% by weight of the pharmaceutical composition;
d) an enteric coat component comprising about 0.01 to about 20% by weight of the pharmaceutical composition;
e) optional glidant component comprising about 0.01 to about 20% by weight of the pharmaceutical composition;
f) Optional plasticizer component comprising about 0.01 to about 3% by weight of the pharmaceutical composition;
g) an optional neutralizer component comprising about 0.01 to about 1.5% by weight of the pharmaceutical composition;
h) any surfactant component comprising about 0.001 to about 1.0% by weight of the pharmaceutical composition;
i) an optional lubricant component comprising about 0.01 to about 5.0% by weight of the pharmaceutical composition, wherein the active drug is of formula I:

(Where:
R ¹ is hydrogen, alkyl of 1-6 carbon atoms, alkanoyl of 2-6 carbon atoms, or carboarylalkoxy of 7-11 carbon atoms;
R ² and R ³ are each independently hydrogen, hydroxy, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, carboxamide, carboalkoxy of 2-6 carbon atoms, 1-6 carbon atoms Perfluoroalkyl, cyano, 1-6 carbon atom alkanesulfonamide, 1-6 carbon atom alkanesulfonyl, 1-6 carbon atom alkaneamide, amino, 1-6 carbon atom alkylamino, 1 per alkyl moiety 6 carbon atoms dialkylamino, 1-6 carbon atoms perfluoroalkoxy, 2-6 carbon atoms alkanoyloxy, 2-6 carbon atoms alkanoyl, 6-8 carbon atoms aroyl, 5-7 carbon atoms aryl, aryl C ₆ -C ₁₃ alkylaryl group having 5 to 7 carbon atoms in the moiety, 5- to 7-membered heteroaryl group or f, A 6-13 membered alkylheteroaryl group having 5-7 members in the teloaryl moiety, wherein any R ² or R ³ substituent having an aryl or heteroaryl moiety is optionally an aryl or heteroaryl moiety above, halogen atom, C ₁ -C ₆ alkyl or C ₁ -C ₆ may be substituted with 1-3 substituents independently selected from alkoxy groups;
R ⁴ and R ⁵ are independently hydrogen or alkyl of 1 to 6 carbon atoms, or R ⁴ and R ⁵ together with the carbon to which they are attached, a 4 to 8 carbon atom cycloalkane, 4 A cycloalkene of ˜8 carbon atoms, a bridged bicyclic alkane of 5-10 carbon atoms, a bridged bicyclic alkene of 5-10 carbon atoms, forming a pyran or thiopyran in which the sulfur atom is optionally oxidized to a sulfoxide or sulfone Wherein the cyclic moiety formed by R ⁴ and R ⁵ is optionally 1-3 substituted independently selected from halogen atoms, C ₁ -C ₆ alkyl groups, or C ₁ -C ₆ alkoxy groups May be substituted with a group;
R ⁶ and R ⁷ are each independently hydrogen or alkyl of 1 to 6 carbon atoms;
n is 1 or 2; and the dashed line represents an optional double bond) or a pharmaceutical composition having a pharmaceutically acceptable salt thereof. R ² is hydrogen, halogen, cyano, perfluoroalkyl of 1 to 3 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkane of 1 to 6 carbon atoms 2. A pharmaceutical composition according to claim 1 which is sulfonyl or aryl of 5 to 7 carbon atoms. R ² is hydrogen, halogen, cyano, alkoxy of 1 to 3 carbon atoms, phenyl or trifluoromethyl, pharmaceutical composition according to claim 1,. R ³ is hydrogen, halogen, cyano, 1 to 6 carbon atoms perfluoroalkyl, 1 to 6 carbon atoms alkyl, 1 to 6 carbon atoms alkoxy, 2 to 6 carbon atoms alkanoyl, 1 to 6 carbon atoms alkane The pharmaceutical composition according to any one of claims 1 to 3, which is sulfonyl or aryl having 5 to 7 carbon atoms. The pharmaceutical composition according to any one of claims 1 to ³ , wherein R3 is hydrogen, halogen, cyano, alkoxy of 1 to 3 carbon atoms, phenyl, or trifluoromethyl. R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cycloalkane or cycloalkene moiety of 5-8 carbon atoms, wherein one or more of these carbon atoms are optionally 1 6. The pharmaceutical composition according to any one of claims 1 to 5, which is substituted by alkyl of -4 carbon atoms. The pharmaceutical composition according to any one of claims 1 to 5, wherein R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 5-7 carbon atom cycloalkane moiety. The pharmaceutical composition according to any one of claims 1 to 7, wherein R ⁶ and R ⁷ are each hydrogen.   The pharmaceutical composition according to any one of claims 1 to 8, wherein n is 1. R ² and R ³ are independently selected from hydrogen, halo, trifluoromethyl, phenyl, or alkoxy of 1 to 3 carbon atoms, R ¹ , R ⁶ , and R ⁷ are each hydrogen and n is 1 And R ⁴ and R ⁵ together with the carbon atom to which they are attached form cyclopentane, cyclohexane, or cycloheptane.   The active drug is (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1 -Ij] The pharmaceutical composition according to claim 1, which is quinoline hydrochloride. a) the active drug comprises from about 15 to about 25% by weight of the pharmaceutical composition;
b) the filler component comprises about 50 to about 70% by weight of the pharmaceutical composition;
c) comprises from about 0.5 to about 3% by weight of the pharmaceutical composition when optional seal coat ingredients are present;
d) the enteric coat component comprises from about 5 to about 15% by weight of the pharmaceutical composition;
e) comprises from about 0.01 to about 1% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.1 to about 1.5% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.01 to about 0.8% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) comprises from about 0.005 to about 0.05% by weight of the pharmaceutical composition when optional surfactant component is present;
i) constitutes from about 1 to about 4% by weight of the pharmaceutical composition when optional lubricant components are present;
The pharmaceutical composition according to any one of claims 1 to 11. a) the active drug comprises about 20 to about 22% by weight of the pharmaceutical composition;
b) the filler component comprises about 60 to about 66% by weight of the pharmaceutical composition;
c) comprises from about 1 to about 2% by weight of the pharmaceutical composition when optional seal coat ingredients are present;
d) the enteric coat component comprises from about 8 to about 12% by weight of the pharmaceutical composition;
e) comprises from about 0.1 to about 0.3% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.5 to about 1.0% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.05 to about 0.3% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) comprises from about 0.005 to about 0.025% by weight of the pharmaceutical composition when optional surfactant component is present;
i) constitutes from about 2.5 to about 3.5% by weight of the pharmaceutical composition when optional lubricant components are present;
The pharmaceutical composition according to any one of claims 1 to 11. a) the active drug comprises about 30 to about 40% by weight of the pharmaceutical composition;
b) the filler component comprises about 40 to about 50% by weight of the pharmaceutical composition;
c) comprises from about 2 to about 3% by weight of the pharmaceutical composition when optional seal coat ingredients are present;
d) the enteric coat component comprises from about 12 to about 16% by weight of the pharmaceutical composition;
e) comprises from about 0.1 to about 3% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.5 to about 2.0% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.03 to about 0.3% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) constitutes from about 0.001 to about 0.3% by weight of the pharmaceutical composition when any surfactant component is present;
i) comprises from about 2.0 to about 3.5% by weight of the pharmaceutical composition when optional lubricant components are present;
The pharmaceutical composition according to any one of claims 1 to 11.   The pharmaceutical composition according to any one of claims 11 to 14, wherein a glidant component, a plasticizer component, a neutralizer component, a surfactant component, and a lubricant component are each present.   Filler component is microcrystalline cellulose, lactose, starch, carboxymethylcellulose, cellulose gum, polyethylene glycol, substituted cellulose, ethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, calcium phosphate, anhydrous dicalcium phosphate, metal aluminosilicate, magnesium aluminometasilicate , Sugar or carbohydrate containing compound, mannitol, sucrose, maltodextrin, sorbitol, starch, xylitol, metal phosphate, metal carbonate, and magnesium carbonate. A pharmaceutical composition according to 1.   The pharmaceutical composition according to any one of claims 1 to 15, wherein the filler component comprises microcrystalline cellulose.   The enteric coat component comprises one or more of methacrylic copolymers, methacrylic acid copolymers, HPMC-containing enteric coating systems, CAP, HPMCP, acrylic polymers, or other acrylate-, methacrylate, or cellulose acetate phthalate-based coats. The pharmaceutical composition as described in any one of Claims 1-17 containing.   The pharmaceutical composition according to any one of claims 1 to 17, wherein the enteric coat component comprises a methacrylic polymer having an anionic functional group.   Mono- and di-glycerides, talc, silicon dioxide, stearic acid, starch, powdered cellulose, lactose, stearate, calcium phosphate, magnesium carbonate, magnesium oxide, silicate, and silicon dioxide aerogel when a glidant component is present 20. A pharmaceutical composition according to any one of the preceding claims comprising one or more of   20. A pharmaceutical composition according to any one of claims 1 to 19, wherein the glidant component comprises mono- and di-glycerides.   The plasticizer component is triethyl citrate, dibutyl sebecate, polyethylene glycol, propylene glycol, triacetin, sorbitol, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, dibutyl phthalate, triethyl citrate, and triethanolamine The pharmaceutical composition according to any one of claims 1 to 21, comprising one or more of:   The pharmaceutical composition according to any one of claims 1 to 21, wherein the plasticizer component comprises triethyl citrate. Neutralizer component, NaOH, KOH, and NH ₄ comprising one or more of OH, pharmaceutical composition according to any one of claims 1 to 23.   24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the plasticizer component comprises NaOH.   The surfactant component is one of polysorbate 80, sodium lauryl sulfate, sucrose palmitate, poloxamer, sodium doxate, and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sucrose fatty acid ester, and sorbitan fatty acid ester 26. The pharmaceutical composition according to any one of claims 1 to 25 comprising or more.   26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the surfactant component comprises polysorbate 80.   The lubricant component is talc, metal stearate, silicon dioxide, sodium stearyl fumarate, fatty acid ester, fatty acid, fatty alcohol, glyceryl behenate, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, metal lauryl sulfate, 28. The pharmaceutical composition according to any one of claims 1 to 27, comprising one or more of silica and sodium chloride.   28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the lubricant component comprises talc. Filler component is microcrystalline cellulose, lactose, starch, carboxymethylcellulose, cellulose gum, polyethylene glycol, substituted cellulose, ethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, calcium phosphate, anhydrous dicalcium phosphate, metal aluminosilicate, magnesium aluminometasilicate Including one or more of: a sugar or carbohydrate containing compound, mannitol, sucrose, maltodextrin, sorbitol, starch, xylitol, metal phosphate, metal carbonate, and magnesium carbonate;
Enteric coating component is one or more of methacrylic copolymer, methacrylic acid copolymer type C, HPMC-containing enteric coating system, CAP, HPMCP, acrylic polymer, or other acrylate-, methacrylate, or cellulose acetate phthalate-based coats Including the above;
Mono- and di-glycerides, talc, silicon dioxide, stearic acid, starch, powdered cellulose, lactose, stearate, calcium phosphate, magnesium carbonate, magnesium oxide, silicate, and dioxide when optional glidant components are present Including one or more of silicon aerogels;
When any plasticizer component is present, triethyl citrate, dibutyl sebecate, polyethylene glycol, propylene glycol, triacetin, sorbitol, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, dibutyl phthalate, triethyl citrate, and Including one or more of triethanolamine;
Including one or more of NaOH, KOH, and NH ₄ OH when optional neutralizer components are present;
Polysorbate 80, sodium lauryl sulfate, sucrose palmitate, poloxamer, doxate sodium, and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sucrose fatty acid ester, and sorbitan fatty acid when optional surfactant components are present Including one or more of esters; and when optional lubricant components are present, talc, metal stearate, silicon dioxide, sodium stearyl fumarate, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oil , Paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, metal lauryl sulfate, Aerosil 200, and one or more of sodium chloride,
The pharmaceutical composition according to any one of claims 11 to 14. The filler component comprises microcrystalline cellulose;
The enteric coat component comprises a methacrylic copolymer having an anionic functional group;
When optional glidant components are present, including mono- and di-glycerides;
Including triethyl citrate when the optional plasticizer component is present;
Including NaOH when optional neutralizer components are present;
Including polysorbate 80 when the optional surfactant component is present; and including talc when the lubricant component is present;
The pharmaceutical composition according to any one of claims 11 to 14.   32. The pharmaceutical composition according to any one of claims 1-31, comprising from about 0.5 mg to about 5.0 mg of active drug.   32. The pharmaceutical composition according to any one of claims 1-31, comprising from about 1.0 mg to about 3.0 mg of active drug.   32. The pharmaceutical composition according to any one of claims 1-31, comprising from about 20 mg to about 30 mg of active drug.   32. The pharmaceutical composition according to any one of claims 1-31, comprising from about 50 mg to about 100 mg of active drug.   32. The pharmaceutical composition according to any one of claims 1-31, comprising from about 70 mg to about 80 mg of active drug.   32. The pharmaceutical composition according to any one of claims 1-31, comprising from about 75 mg to about 125 mg of active drug.   32. The pharmaceutical composition according to any one of claims 1-31, containing from about 90 mg to about 110 mg of active drug.   39. The pharmaceutical composition according to any one of claims 1 to 38, comprising a plurality of enteric coated pellets.   40. The pharmaceutical composition of claim 39, wherein the enteric coated pellets are present in a capsule. A method for preparing a pharmaceutical composition comprising a plurality of enteric coated pellets, wherein the pellets comprise the pharmaceutical composition of claim 11,
a) preparing uncoated pellets containing the filler and the active drug;
b) optionally adding a subcoat to these uncoated pellets; and c) adding an enteric coating to these pellets. further,
d) a given dose of (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7, 42. The method of claim 41, further comprising the step of filling capsules with the pellets to obtain 1-ij] quinoline hydrochloride. The step (a)
i) mixing the filler and the active drug to form a mixture;
43. The method of claim 41 or 42, comprising: ii) wet granulating the mixture to form a granulate; and iii) extruding and granulating the granulate. The step (c)
i) a step of preparing a suspension comprising the enteric coat, the plasticizer, the neutralizing agent, and the surfactant;
44. The method of any one of claims 41 to 43, comprising ii) spraying the suspension onto the pellets.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 0.5 mg to about 5.0 mg of active drug.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 1.0 mg to about 3.0 mg of active drug.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 20 mg to about 30 mg of active drug.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 24.0 mg to about 26.0 mg of active drug.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 50 mg to about 100 mg of active drug.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 70 mg to about 80 mg of active drug.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 75 mg to about 125 mg of active drug.   45. The method of any one of claims 41 to 44, wherein the composition contains from about 90 mg to about 110 mg of active drug.   53. The product of the method of any one of claims 41-52. A pharmaceutical composition comprising a plurality of enteric coated pellets, wherein the pellets are
a) an active drug comprising about 20 to about 40% by weight of the pharmaceutical composition;
b) a filler component comprising about 40 to about 70% by weight of the pharmaceutical composition;
c) optional sealcoat component, if present, comprising from about 1 to about 3% by weight of the pharmaceutical composition;
d) an enteric coat component comprising about 8 to about 16% by weight of the pharmaceutical composition;
e) any glidant component that, if present, comprises from about 0.1 to about 3% by weight of the pharmaceutical composition;
f) any plasticizer component that, if present, comprises about 0.5 to about 2.0% by weight of the pharmaceutical composition;
g) any neutralizer component that, when present, comprises from about 0.03 to about 0.3% by weight of the pharmaceutical composition;
h) any surfactant component that, when present, comprises about 0.001 to about 0.3% by weight of the pharmaceutical composition;
i) If present, comprises an optional lubricant component comprising about 2.0 to about 3.5% by weight of the pharmaceutical composition, wherein the active drug is (9aR, 12aS) -4,5,6,7 , 9, 9a, 10, 11, 12, 12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydrochloride. The filler component comprises microcrystalline cellulose;
The enteric coat component comprises a methacrylic copolymer having an anionic functional group;
When a glidant component is present, including mono- and di-glycerides;
Including triethyl citrate when a plasticizer component is present;
Including NaOH when a neutralizer component is present;
Including a polysorbate 80 when a surfactant component is present;
When the lubricant component is present, including talc,
55. A pharmaceutical composition according to claim 54.   56. The pharmaceutical composition according to claim 54 or 55, wherein each of said components (c), (e), (f), (g), (h), and (i) is present in the composition.   57. The pharmaceutical composition according to any one of claims 54 to 56, containing from about 0.5 mg to about 5.0 mg of active drug.   57. A composition according to any one of claims 54 to 56, containing from about 1.0 mg to about 3.0 mg of active drug.   57. The composition according to any one of claims 54 to 56, comprising from about 20 mg to about 30 mg of active drug.   57. A composition according to any one of claims 54 to 56, containing from about 24.0 mg to about 26.0 mg of active drug.   57. The composition according to any one of claims 54 to 56, comprising from about 50 mg to about 100 mg of active drug.   57. The composition according to any one of claims 54 to 56, comprising from about 70 mg to about 80 mg of active drug.   57. The composition according to any one of claims 54 to 56, comprising from about 75 mg to about 125 mg of active drug.   57. The composition according to any one of claims 54 to 56, comprising from about 90 mg to about 110 mg of active drug. a) the active drug comprises from about 30 to about 45% by weight of the pharmaceutical composition;
b) the filler component comprises about 40 to about 60% by weight of the pharmaceutical composition;
c) comprises from about 0.5 to about 3% by weight of the pharmaceutical composition when optional seal coat ingredients are present;
d) the enteric coat component comprises from about 5 to about 15% by weight of the pharmaceutical composition;
e) comprises from about 0.1 to about 2% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.1 to about 1.5% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.01 to about 0.8% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) comprises from about 0.005 to about 0.05% by weight of the pharmaceutical composition when optional surfactant component is present;
i) constitutes from about 1 to about 4% by weight of the pharmaceutical composition when optional lubricant components are present;
The pharmaceutical composition according to claim 11. a) the active drug comprises about 50 to about 70% by weight of the pharmaceutical composition;
b) the filler component comprises from about 10 to about 30% by weight of the pharmaceutical composition;
c) comprises from about 0.5% to about 3% by weight of the pharmaceutical composition when the optional seal coat component is present;
d) the enteric coat component comprises from about 5 to about 15% by weight of the pharmaceutical composition;
e) comprises from about 0.1 to about 2% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.1 to about 1.5% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.01 to about 0.8% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) comprises from about 0.005 to about 0.05% by weight of the pharmaceutical composition when optional surfactant component is present;
i) constitutes from about 1 to about 4% by weight of the pharmaceutical composition when optional lubricant components are present;
The pharmaceutical composition according to claim 11. a) the active drug comprises about 60 to about 70% by weight of the pharmaceutical composition;
b) the filler component comprises from about 10 to about 30% by weight of the pharmaceutical composition;
c) comprises from about 0.5 to about 3% by weight of the pharmaceutical composition when optional seal coat ingredients are present;
d) the enteric coat component comprises from about 5 to about 15% by weight of the pharmaceutical composition;
e) comprises from about 0.1 to about 2% by weight of the pharmaceutical composition when the optional glidant component is present;
f) comprises from about 0.1 to about 1.5% by weight of the pharmaceutical composition when the optional plasticizer component is present;
g) comprises from about 0.01 to about 0.8% by weight of the pharmaceutical composition when the optional neutralizing agent component is present;
h) comprises from about 0.005 to about 0.05% by weight of the pharmaceutical composition when optional surfactant component is present;
i) constitutes from about 1 to about 4% by weight of the pharmaceutical composition when optional lubricant components are present;
The pharmaceutical composition according to claim 11. Filler component is microcrystalline cellulose, lactose, starch, carboxymethylcellulose, cellulose gum, polyethylene glycol, substituted cellulose, ethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, calcium phosphate, anhydrous dicalcium phosphate, metal aluminosilicate, magnesium aluminometasilicate Including one or more of: a sugar or carbohydrate containing compound, mannitol, sucrose, maltodextrin, sorbitol, starch, xylitol, metal phosphate, metal carbonate, and magnesium carbonate;
The enteric coat component comprises one or more of methacrylic copolymers, methacrylic acid copolymers, HPMC-containing enteric coating systems, CAP, HPMCP, acrylic polymers, or other acrylate-, methacrylate, or cellulose acetate phthalate-based coats. Including;
Mono- and di-glycerides, talc, silicon dioxide, stearic acid, starch, powdered cellulose, lactose, stearate, calcium phosphate, magnesium carbonate, magnesium oxide, silicate, and dioxide when optional glidant components are present Including one or more of silicon aerogels;
When any plasticizer component is present, triethyl citrate, dibutyl sebecate, polyethylene glycol, propylene glycol, triacetin, sorbitol, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, dibutyl phthalate, triethyl citrate, and Including one or more of triethanolamine;
Including one or more of NaOH, KOH, and NH ₄ OH when optional neutralizer components are present;
Polysorbate 80, sodium lauryl sulfate, sucrose palmitate, poloxamer, doxate sodium, and polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sucrose fatty acid ester, and sorbitan fatty acid when optional surfactant components are present Including one or more of esters; and when optional lubricant components are present, talc, metal stearate, silicon dioxide, sodium stearyl fumarate, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oil , Paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol, metal lauryl sulfate, Aerosil 200, and one or more of sodium chloride,
68. A pharmaceutical composition according to any one of claims 65 to 67. The filler component comprises microcrystalline cellulose;
The enteric coat component comprises a methacrylic copolymer having an anionic functional group;
When optional glidant components are present, including mono- and di-glycerides;
Including triethyl citrate when the optional plasticizer component is present;
Including NaOH when optional neutralizer components are present;
Including polysorbate 80 when the optional surfactant component is present; and including talc when the lubricant component is present;
69. A pharmaceutical composition according to claim 68.   70. The pharmaceutical composition according to any one of claims 65 to 69, containing from about 50 mg to about 200 mg of active drug.   70. The pharmaceutical composition according to any one of claims 65-69, which contains from about 50 mg to about 750 mg of active drug.   70. The pharmaceutical composition according to any one of claims 65-69, which contains from about 100 mg to about 750 mg of active drug.   70. The pharmaceutical composition according to any one of claims 65-69, which contains from about 200 mg to about 750 mg of active drug.   70. The pharmaceutical composition according to any one of claims 65-69, which contains from about 300 mg to about 750 mg of active drug.   About 2 mg, about 4 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, or about 750 mg of activity 70. The pharmaceutical composition according to any one of claims 65 to 69, comprising a drug.   76. A pharmaceutical composition according to any one of claims 65 to 75 comprising a plurality of enteric coated pellets.   77. The pharmaceutical composition of claim 76, wherein the enteric coated pellet is present in a capsule.   78. The pharmaceutical composition according to any one of claims 65 to 77, further comprising a sustained release component.   79. The pharmaceutical composition of claim 78, wherein the sustained release component is a coating disposed between the optional seal coat component and the enteric coat component.   80. The pharmaceutical composition of claim 78 or 79, wherein the sustained release component comprises a controlled release excipient.   The controlled release excipient is gelatin, shellac, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), ethylcellulose (EC), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), methacrylic acid / methyl methacrylate copolymer 81. The pharmaceutical composition of claim 80, comprising one or more of:, polyvinyl acetate phthalate (PVAP), glyceryl behenate, paraffin, or carnauba wax.   The pharmaceutical composition according to claim 11, further comprising a sustained release component.   83. The pharmaceutical composition according to claim 82, wherein the sustained release component is a coating disposed between the optional seal coat component and the enteric coat component.   84. The pharmaceutical composition of claim 82 or 83, wherein the sustained release coating comprises a controlled release excipient.   The controlled release excipient is gelatin, shellac, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), ethylcellulose (EC), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), methacrylic acid / methyl methacrylate copolymer 85. A pharmaceutical composition according to claim 84, comprising one or more of polyvinyl acetate phthalate (PVAP), glyceryl behenate, paraffin, or carnauba wax.   Enteric coated forms of (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7 , 1-ij] A pharmaceutical composition comprising quinoline hydrochloride.   90. The pharmaceutical composition according to claim 86, further comprising a sustained release coating.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition comprises 100 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ An average AUCss of approximately 33.23 hr * ng / mL ± 20% for a dosage of 1,4] diazepino [6,7,1-ij] quinoline, or approximately proportional to a total dose other than 100 mg In human schizophrenic patients with respective mean AUC values, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1, 4] Zia Pinot [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 90. The pharmaceutical composition of claim 88, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition is 150 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dose about 54.88 hr * ng / mL ± 20% average AUCss, or about this for total doses other than 150 mg In patients with human schizophrenia having respective proportional average AUC values, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [ ] [1,4] diazepino [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 92. The pharmaceutical composition according to claim 90, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition comprises 250 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dosage approximately 173.49 hr * ng / mL ± 20% average AUCss, or approximately this for a total dose other than 250 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta in human schizophrenia patients with respective proportional average AUC values c] [1,4] diazepino [6,7,1-ij] pharmaceutical composition is effective to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 94. The pharmaceutical composition of claim 92, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride comprising 25 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dosage approximately 8.73 hr * ng / mL ± 20% average AUCss, or approximately this for a total dose other than 25 mg In healthy humans with respective average AUC values that are proportional, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1, 4] Azepino [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 95. The pharmaceutical composition of claim 94, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, said composition comprising 50 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dose of about 26.49 hr * ng / mL ± 20% average AUCss, or about this for total doses other than 50 mg In healthy humans with respective average AUC values that are proportional, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1, 4 Diazepino [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 99. The pharmaceutical composition of claim 96, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition comprises 75 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dose about 24.95 hr * ng / mL ± 20% average AUCss, or about this for total doses other than 75 mg In healthy humans with respective average AUC values that are proportional, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1, 4 Diazepino [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 99. The pharmaceutical composition of claim 98, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition comprises 100 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dosage approximately 62.76 hr * ng / mL ± 20% average AUCss, or approximately this for total doses other than 100 mg In healthy humans with respective proportional average AUC values, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1 4] diazepino [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 101. The pharmaceutical composition of claim 100, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition is 150 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dose of about 109.50 hr * ng / mL ± 20% average AUCss, or about this for total doses other than 150 mg In healthy humans with respective average AUC values that are proportional, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [c] [ , 4] diazepino [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 103. The pharmaceutical composition of claim 102, wherein the hydrochloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition comprises 250 mg (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [ 1,4] diazepino [6,7,1-ij] quinoline hydrochloride dose about 234.75 hr * ng / mL ± 20% average AUCss, or about this for total doses other than 250 mg In healthy humans with respective average AUC values that are proportional, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [c] [ , 4] diazepino [6,7,1-ij] effective pharmaceutical compositions which are to produce a mean plasma concentration profile for quinoline.   Said (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline 105. The pharmaceutical composition of claim 104, wherein the hydrochloride is present in an enteric coated form. (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A pharmaceutical composition comprising chloride, wherein the composition is effective to produce a T _max of about 4 hours to about 6.5 hours in a healthy human or patient. About 2 to about 150 mg of (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7, 1-ij] a unit dosage form comprising quinoline hydrochloride, (9aR, 12aS) -4,5,6,7,9,9a, 10,11 about 4 to about 8 hours after administration to a subject. , 12, 12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline unit dosage form that yields C _max .   A certain amount of (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij A unit dosage form comprising quinoline hydrochloride, the dosage form comprising a degradable coating, (9aR, 12aS) -4,5,6,7,9,9a, 10,11, The coating degrades so that less than 30% of 12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydrochloride is released after 2 hours. A unit dosage form characterized by A unit dosage form of a drug comprising:
(9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro With chloride,
A degradable coating comprising (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6 7,1-ij] A unit dosage form comprising a coating characterized in that less than 30% of the quinoline hydrochloride degrades to be released after 2 hours. A unit dosage form of a drug comprising:
(9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro With chloride,
A degradable coating comprising (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6 7,1-ij] quinoline hydrochloride is released, and after about 4 to about 8 hours after administration, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a- A unit dosage form comprising a coating characterized by degrading to produce a C _max of decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline. Uniform dosages of (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1- ij] a unit dosage form of a drug having quinoline hydrochloride, characterized by a dissolution profile when administered orally, (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12 , 12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydrochloride is (9aR, 12aS) -4,5,6,7,9,9a, 10, The C _max of 11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline occurs from about 4 to about 8 hours after administration to the subject. Released unit dosage form.   111. The unit dosage form according to any one of claims 107 to 111, wherein the dosage form comprises a plurality of enteric coated pellets. (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A method for preparing a formulation comprising chloride, comprising:
(9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro Providing pellets comprising chloride; and an enteric coating comprising an enteric coating polymer in an amount that provides an increase of about 12% to about 22% enteric coating polymer relative to the weight of the uncoated pellets. A method comprising the step of adding to. (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A method for preparing a formulation comprising chloride, comprising:
(9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro Supplying pellets containing chloride; and adding an enteric coating to these pellets after administration of the formulation (9aR, 12aS) -4,5,6,7,9,9a, 10, 11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydrochloride is about 4 to about 8 hours after administration to a subject (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline C _max is generated. Released as Sea urchin, a method comprising the coating step of decomposing.   The coating was (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6] after 2 hours. 115. The method of claim 114, wherein the method achieves a dissolution profile characterized by less than 30% release of 7,1-ij] quinoline hydrochloride.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a characterized by the maximum peak followed by the lower value secondary peak. A formulation that produces serum levels of decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydrochloride.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro 117. The formulation of claim 116, wherein the chloride is present in an enteric coated form.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A chloride-containing formulation comprising (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [c] [ A formulation that provides release of [1,4] diazepino [6,7,1-ij] quinoline hydrochloride.   (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1,4] diazepino [6,7,1-ij] quinoline hydro A chloride-containing formulation comprising (9aR, 12aS) -4,5,6,7,9,9a, 10,11,12,12a-decahydrocyclopenta [c] [1 after administration to a subject , 4] Diazepino [6,7,1-ij] quinoline hydrochloride release delayed.

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